AU2004212029B2 - Method for the production of bicyclic aromatic amino acids and intermediate products thereof - Google Patents

Method for the production of bicyclic aromatic amino acids and intermediate products thereof Download PDF

Info

Publication number
AU2004212029B2
AU2004212029B2 AU2004212029A AU2004212029A AU2004212029B2 AU 2004212029 B2 AU2004212029 B2 AU 2004212029B2 AU 2004212029 A AU2004212029 A AU 2004212029A AU 2004212029 A AU2004212029 A AU 2004212029A AU 2004212029 B2 AU2004212029 B2 AU 2004212029B2
Authority
AU
Australia
Prior art keywords
denotes
atoms
formula
alkyl
mono
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
AU2004212029A
Other versions
AU2004212029A1 (en
Inventor
Bernd Neff
Matthias Wiesner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of AU2004212029A1 publication Critical patent/AU2004212029A1/en
Application granted granted Critical
Publication of AU2004212029B2 publication Critical patent/AU2004212029B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

A multi-stage process is claimed for preparing 2-amino-3-(2-(substituted ethyl)-3-oxo-3,4-dihydro-2H-benz-(1,4)-oxazin-6-yl)-propionic acid derivatives (I), starting from 5-oxo-tetrahydrofuran-2-carboxylic acid and based on construction and cyclization of new 2-(4-(2-amino-2-carboxy-ethyl)-2-nitrophenoxy)-pentanedicarboxylate diesters (VII). Preparation of benzoxazinones of formula (I) or their derivatives, solvates or stereoisomers involves: (1) reacting 5-oxo-tetrahydrofuran-2-carboxylic acid with a benzylating or alkylating agent of formula R 7>-L (II) to give a hydroxy-glutaric acid diester of formula R 7>OCO-CH 2CH 2CH(OH)-COOR 7>(III); (2) optionally reacting (III) with a sulfonating agent of formula R 8>-L (IV) to give an O-sulfonyl derivative of formula R 7>OCO-CH 2CH 2CH(OR 8>)-COOR 7>(V); (3) reacting (III) or (V) with a nitrophenol derivative of formula (VI) to give an O-(nitrophenoxy) compound of formula (VII); (4) converting (VII) into benzoxazinyl-propionic acid derivative of formula (VIII); (5) reacting (VIII) (optionally after conversion of the COOH group into COL') with R 5>-H (IX) or R 6>-NH 2(X) to give (I); and (6) optionally interconverting groups R 2>in the product by reaction of (I; R 2>= H) with L-R 1>0>, L-CO-R 1>0>, L-COOR 6>, L-COOR 1>0>, R 1>0>-NCO or R 1>0>-SO 2L. [Image] R 1>H, 1-6C alkyl or benzyl; R 2>R 1>0>, COR 1>0>, COOR 6>, COOR 1>0>, CONHR 1>0>, SO 2R 6>or SO 2R 1>0>; R 3>H or 1-6C alkyl; R 4>H, halo, OA, NHR 1>0>, N(R 1>0>) 2, -NH-acyl, -O-acyl, CN, NO 2, OR 1>0>, SR 1>0>, R 2>or CONHR 1>0>; R 5>H, NH 2, C(=NH)NH 2or NHC(=NH)NH 2(where primary amino groups are optionally protected or optionally substituted (os) by 1-3 of R 1>0>, COR 1>0>, COOR 1>0>or SO 2R 1>0>); or R 6>; X : direct bond or NH; R 6>mono- or bicyclic, saturated, unsaturated or aromatic heterocycle containing 1-4 N, O and/or S atoms (os by 1-3 of halo, A, COA, CN, COOH, COOA, CONHA, NO 2, =NH or O); R 9>H, halo, OA, NHA, NAA', NH-acyl, O-acyl, CN, NO 2, SA, SOA, SO 2A, SO 2Ph' or SO 3H; R 1>0>H, A, Ar or 7-14C aralkylene; A, A' : H; or 1-15C alkyl or 3-15C cycloalkyl (both os by 1-3 R 6>and optionally having 1-3 CH 2groups replaced by N, O and/or S); Ar : mono- or bicyclic aromatic ring system (os by 1-3 of A and/or R 9>and optionally containing 1-4 of N, O and/or S); Ph' : phenyl (os by 1-3 A); R 7>benzyl or 1-6C alkyl; L : Cl, Br, I or free of functionally modified OH; R 8>1-6C alkylsulfonyl or 6-10C arylsulfonyl; L' : as for L but not free OH. Independent claims are included for: (a) the intermediates (VII) and their salts, solvates and stereoisomers as new compounds; and (b) the preparation of (VII) by the first three stages of the above process. ACTIVITY : Thrombolytic; Anticoagulant; Cardiant; Antiarteriosclerotic; Antiinflammatory; Cerebroprotective; Antianginal; Cytostatic; Osteopathic; Ophthalmological; Antidiabetic; Antirheumatic; Antiarthritic; Antiulcer; Antipsoriatic; Vasotropic; Virucide; Antibacterial; Fungicide; Nephrotropic; Vulnerary. MECHANISM OF ACTION : Integrin inhibitor; Vitronectin receptor antagonist; Angiogenesis inhibitor.

Description

Process for the preparation of bicyclic aromatic amino acids and intermediates thereof 5 Bicyclic aromatic amino acids have proven to be suitable templates for the preparation of integrin antagonists. Compounds from this class of substances are known, for example, from WO 94/29273, WO 96/00730 and WO 96/18602 or known from 10 WO 98/35949 Typical representatives of these substances contain two stereocentres and thus occur in four diastereomeric forms. For a suitable preparation process of such compounds with optimised overall yield, it is particularly important 15 that the reaction be carried out stereoselectively since complex chiral puri fication can then be avoided. The invention seeks to find a novel process for the preparation of compounds, in particular substances which are described in 20 WO 98/35949 It has been found that reactive derivatives of hydroxyglutaric acid, which facilitate stereoselective construction of the benzoxazinone skeleton by reaction with suitable tyrosine derivatives and result in diastereomerically 25 pure products, can be prepared from enantiomerically pure glutamic acid. In contrast to the synthetic route described in WO 98/35949, the process according to the invention proceeds with virtually no racemisation, and resolution of the diastereomers by chromatography or crystallisation can be avoided. 30 The invention relates to a process for the preparation of compounds of the formula I 35 WO 2004/072054 PCT/EP2004/000210 -2 HR3 O O O R1 H O HN R2 5 R5 (CH2)2 R4 0 in which R1 denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or benzyl, 10 R 2 denotes R 1 0 , CO-R'", COOR , COOR'", CONHR", S0 2
R
6 or
SO
2 Rla, R 3 denotes H or alkyl having 1-6 C atoms, R 4 denotes H, Hal, OA, NHR' 1 , N(R'") 2 , -NH-acyl, -0-acyl, CN, NO 2 ,
OR
10 , SR' 1 , R 2 or CONHR 1 ", 15 R 5 denotes NH 2 , H 2 N-C(=NH) or H 2 N-(C=NH)-NH, where the primary I amino groups may also be provided with conventional amino-pro tecting groups, or may be mono-, di- or trisubstituted by R'",
CO-R
1 0 , COOR'" or SO2R', or R , 20 x is absent or denotes NH, R" 6 denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, 0 and/or S atoms, which may be un substituted or mono-, di- or trisubstituted by Hal, A, -CO-A, OA, CN, COOH, COOA, CONHA, NO 2 , =NH or =0, 25 R 9 denotes H, Hal, OA, NHA, NAA', NHacyl, Oacyl, CN, NO 2 , SA, SOA, SO 2 A, SO 2 Ph or SO 3 H, R10 denotes H, A, Ar or aralkylene having 7-14 C atoms, A, A' each, independently of one another, denote H or alkyl or cycloalkyl having 1-15 C atoms, each of which is unsubstituted or mono-, di 30 or trisubstituted by R 9 and in which one, two or three methylene groups may be replaced by N, 0 and/or S, Ar denotes mono- or bicyclic aromatic ring system having 0, 1, 2, 3 or 4 N, 0 and/or S atoms which is unsubstituted or mono-, di- or tri substituted by A and/or R 9 , 35 Ph denotes phenyl which is unsubstituted or mono-, di- or trisubstitu ted by A, WO 2004/072054 PCT/EP2004/000210 -3 Hal denotes F, Cl, Br or I and, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, 5 where a) 5-oxotetrahydrofuran-2-carboxylic acid is reacted with a compound of the formula 11
R
7 -L 1| 10 in which
R
7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and L denotes Cl, Br, I or a free or reactively functionally modified OH group, 15 to give a compound of the formula IlIl 0 0 R7 0R7 20 OH in which RT 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, 25 b) then a compound of the formula Ill is reacted with a compound of the formula IV
R
8 -L IV in which 30 R8 denotes alkylsulfonyl having 1-6 C atoms or arylsulfonyl having - 6-10 C atoms and L denotes Cl, Br, I or a free or reactively functionally modified OH group, 35 to give a compound of the formula V WO 2004/072054 PCT/EP2004/000210 -4 0 0
R
7 R7 V 5 R O in which RT 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and 10 R 8 denotes alkylsulfonyl having 1-6 C atoms or arylsulfonyl having 6-10 C atoms, c) then a compound of the formula Ill or V is reacted with a compound of the formula VI 15 R3 O 02N O IIR' ONN 20 HO R2 VI R4 in which R1 denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or benzyl, 25 R 2 denotes R 1 0 , CO-R'*, COOR , COOR 10 , CONHR'", S0 2
R
6 or
SO
2 R'",
R
3 denotes H or alkyl having 1-6 C atoms, R 4 denotes H, Hal, OA, NHR 1 ", N(R' 0
)
2 , -NH-acyl, -0-acyl, CN, NO 2 ,
OR
10 , SR'", R 2 or CONHR'", 30 R 6 denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, 0 and/or S atoms, which may be un substituted or mono-, di- or trisubstituted by Hal, A, -CO-A, OA, CN, COOH, COOA, CONHA, NO 2 , =NH or =0,
R
9 denotes H, Hal, OA, NHA, NAA', NHacyl, Oacyl, CN, NO 2 , SA, 35 SOA, SO 2 A, SO 2 Ph or SO 3 H,
R
1 0 denotes H, A, Ar or aralkylene having 7-14 C atoms, WO 2004/072054 PCT/EP2004/000210 -5 A, A' each, independently of one another, denote H or alkyl or cycloalkyl having 1-15 C atoms, each of which is unsubstituted or mono-, di or trisubstituted by R 9 and in which one, two or three methylene groups may be replaced by N, 0 and/or S, 5 Ar denotes mono- or bicyclic aromatic ring system having 0, 1, 2, 3 or 4 N, 0 and/or S atoms which is unsubstituted or mono-, di- or tri substituted by A and/or R 9 , Ph denotes phenyl which is unsubstituted or mono-, di- or trisubstitu ted by A, 10 Hal denotes F, Cl, Br or 1, to give a compound of the formula VII 15 R3 O R7 02N O0R ONH 2 R2 O R4 20 Vil R7 25 in which Ri denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or benzyl, R2 denotes R 1 0 , CO-R', COOR6, COOR 10 , CONHR' 0 , S0 2
R
6 or
SO
2 R'*,
R
3 denotes H or alkyl having 1-6 C atoms, 30 R 4 denotes H, Hal, OA, NHR'", N(R' 0
)
2 , -NH-acyl, -0-acyl, CN, NO 2 ,
OR
1 0 , SR'O, R2 or CONHR", R4 6 denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, 0 and/or S atoms, which may be un substituted or mono-, di- or trisubstituted by Hal, A, -CO-A, OA, CN, COOH, COOA, CONHA, NO 2 , =NH or =0, RT 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, WO 2004/072054 PCT/EP2004/000210 -6 IRS denotes H, Hal, OA, NHA, NAA', NHacyl, Oacyl, CN, NO 2 , SA, SOA, SO 2 A, SO 2 Ph or SO 3 H, R 10 denotes H, A, Ar or aralkylene having 7-14 C atoms, A, A' each, independently of one another, denote H or alkyl or cycloalkyl 5 having 1-15 C atoms, each of which is unsubstituted or mono-, di or trisubstituted by R 9 and in which one, two or three methylene groups may be replaced by N, 0 and/or S, Ar denotes mono- or bicyclic aromatic ring system having 0,.1, 2, 3 or 4 N, 0 and/or S atoms which is unsubstituted or mono-, di- or tri 10 substituted by A and/or R 9 , Ph denotes phenyl which is unsubstituted or mono-, di- or trisubstitu ted by A, Hal denotes F, CI, Br or I, 15 d) then a compound of the formula VII is converted into a compound of the formula VIII H R3 O HN 20 0 N OR1 HO Vill
(CH
2
)
2 0 25 in which R' denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or benzyl, denotes R' 0 , CO-R 1 0 , COOR , COOR' 0 , CONHR 1 0 , S0 2
R
6 or
SO
2 R'*, 30 R 3 denotes H or alkyl having 1-6 C atoms, R 4 denotes H, Hal, OA, NHR 1 ", N(R' 0
)
2 , -NH-acyl, -0-acyl, CN, NO 2 ,
OR
1 0 , SR' 1 , R 2 or CONHR' 0 , RS 6 denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, 0 and/or S atoms, which may be un substituted or mono-, di- or trisubstituted by Hal, A, -CO-A, OA, CN, COOH, COOA, CONHA, NO 2 , =NH or =0, WO 2004/072054 PCT/EP2004/000210 -7
R
9 denotes H, Hal, OA, NHA, NA', NHacyl, Oacyl, CN, NO 2 , SA, SOA, SO 2 A, SO 2 Ph or SO 3 H,
R
1 0 denotes H, A, Ar or aralkylene having 7-14 C atoms, A, A' each, independently of one another, denote H or alkyl or cycloalkyl 5 having 1-15 C atoms, each of which is unsubstituted or mono-, di or trisubstituted by R 9 and in which one, two or three methylene groups may be replaced by N, 0 and/or S, Ar denotes mono- or bicyclic aromatic ring system having 0, 1, 2, 3 or 4 N, 0 and/or S atoms which is unsubstituted or mono-, di- or tri 10 substituted by A and/or R 9 , Ph denotes phenyl which is unsubstituted or mono-, di- or trisubstitu ted by A, Hal denotes F, Cl, Br or I, 15 e) subsequently, if desired, a compound of the formula Vill is converted into a compound of the formula Villa H 20 OL I N OR L O RR2
(CH
2
)
2 Vlla 0 25 in which
R
1 , R 2 , R 3 and R 4 have the meanings indicated under d) and L denotes Cl, Br, I or a reactively functionally modified OH group, 30 e) then a compound of the formula Vill or a compound of the formula Villa is reacted e) i) with a compound of the formula IX 35
R
5 -H IX WO 2004/072054 PCT/EP2004/000210 in which
R
5 denotes NH 2 , H 2 N-C(=NH) or H 2 N-(C=NH)-NH, where the primary amino groups may also be provided with conventional amino protecting groups, or may be mono-, di- or trisubstituted by R'", 5 CO-R'", COOR'" or SO 2 R', in which R' 0 has the meanings indicated for the formula 1, or is reacted 10 e) ii) with a compound of the formula X
R
6
-NH
2 X in which
R
6 denotes a mono- or bicyclic saturated, unsaturated or aromatic 15 heterocycle having 1 to 4 N, 0 and/or S atoms, which may be un substituted or mono-, di- or trisubstituted by Hal, A, -CO-A, OA, CN, COOH, COOA, CONHA, NO 2 , =NH or =0, to give a compound of the formula 1, 20 2 subsequently, if desired, a radical R is converted into another radical R" by reacting a compound of the formula I in which R2 denotes H with a compound selected from the group 25 L-R 10 , L-CO-R 10 , L-COOR 6 , L-COOR'*, R'*-N=C=O, R -SO 2 L,
R
1 0
-SO
2 L, in which R* 10 denotes A, Ar or aralkylene having 7-14 C atoms, A and Ar have the meanings indicated and 30 L denotes Cl, Br, I or a free or reactively functionally modified OH group, and/or a base or acid of the formula I is converted into one of its salts. WO 98/35949 is to be regarded as the closest prior art. The reaction 35 starting from a dibromo compound is carried out therein analogously to the following scheme (Example 8 in WO 98/35949): WO 2004/072054 PCTIEP2004/0002 10 -9 0 0 Br ~K+HO HNO LUI 10 0 KHNy EtO-OC '" Br ~CO-QR -t 15 0 20 ON0 HN ~ IZ EtO-OC 0'' CO M "
N
3 C-~ 25 H 0 N 30 ~0I Nr'II1 HNN 35 WO 2004/072054 PCT/EP2004/000210 -10 In Example 11 of WO 98/35949, the reaction is carried out analogously to the following scheme: 5 Bn-o -JOH D-glutamic acid NH2 HON 1 0 B n - oJ O HH 2 N B r BO17 Br 15Bn-O H 0 25 30 H 0 NIN o-tBu 1 oy, )a HNyO 20 0 H 30 0 N HO ~) T tBu 20 In contrast to the processes described in WO 98/35949, the processes 35 according to the invention surprisingly proceed with high stereospecificity, i.e. no racemisation is evident or the selectivity is > 96%.
WO 2004/072054 PCT/EP2004/000210 - 11 The compounds of the formula I and salts thereof have very valuable pharmacological properties while being well tolerated. In particular, they act as integrin inhibitors, inhibiting, in particular, the interactions of the axv integrin receptors with ligands. The compounds exhibit particular efficacy 5 in the case of integrins av03 and av05. The compounds are very particu larly effective as adhesion receptor antagonists for the vitronectin receptor av03. This action can be demonstrated, for example, by the method described by J.W. Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990). 10 B. Felding-Habermann and D.A. Cheresh describe in Curr. Opin. Cell. Biol. 5, 864 (1993) the significances of the integrins as adhesion receptors for a very wide variety of phenomena and clinical pictures, especially in relation to the vitronectin receptor av0 3 . 15 The dependence of the occurrence of angiogenesis on the interaction bet ween vascular integrins and extracellular matrix proteins is described by P.C. Brooks, R.A. Clark and D.A. Cheresh in Science 264, 569-71 (1994). The possibility of inhibiting this interaction and thus initiating apoptosis 20 (programmed cell death) of angiogenic vascular cells by a cyclic peptide is described by P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T.-Hu, G. Klier and D.A. Cheresh in Cell 79,1157-64 (1994). The experimental evidence that the compounds according to the invention 25 also prevent the attachment of living cells to the corresponding matrix proteins and accordingly also prevent the attachment of tumour cells to matrix proteins can be provided in a cell adhesion test carried out analo gously to the method of F. Mitjans et al., J. Cell Science 108, 2825-2838 (1995). 30 P.C. Brooks et al. in J. Clin. Invest. 96, 1815-1822 (1995) describe cLV03 antagonists for combating cancer and for the treatment of tumour-induced angiogenic diseases. The compounds of the formula I according to the invention can therefore 35 be employed as medicament active ingredients, in particular for the treat- WO 2004/072054 PCT/EP2004/000210 - 12 ment of tumour diseases, osteoporoses, osteolytic diseases and for sup pressing angiogenesis. Compounds of the formula I which block the interaction of integrin recep 5 tors and ligands prevent the spread of tumour cells by metastasis. This is confirmed by the following observations: The spread of tumour cells from a local tumour into the vascular system takes place through the formation of microaggregates (microthrombi) through interaction of the tumour cells with blood platelets. The tumour 10 cells are masked by the protection in the microaggregate and are not rec ognised by the cells of the immune system. The microaggregates are able to attach to vascular walls, simplifying fur ther penetration of tumour cells into the tissue. Since the formation of the microthrombi is promoted by fibrinogen binding 15 to the fibrinogen receptors on activated blood platelets, the GPIla/Illb antagonists can be regarded as effective metastasis inhibitors. Besides the binding of fibrinogen, fibronectin and the Willebrand factor to the fibrinogen receptor of the blood platelets, compounds of the formula 1 20 also inhibit the binding of further adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. In particular, they prevent the formation of blood platelet thrombi and can therefore be employed for the treatment of thromboses, apoplexy, cardiac infarction, inflammation and arteriosclerosis. 25 In particular, the compounds of the formula I can also be used in ophthal mology. The properties of the compounds can also be determined by methods 30 described in EP-A1-0 462 960. The inhibition of the binding of fibrinogen to the fibrinogen receptor can be determined by the method indicated in EP-A1-0 381 033. The thrombocyte aggregation-inhibiting action can be determined in vitro 35 by the method of Born (Nature 4832, 927-929, 1962).
WO 2004/072054 PCT/EP2004/000210 -13 The invention accordingly relates to compounds of the formula I according to Claim 1 and/or physiologically acceptable salts thereof for the prepara tion of a medicament for use as integrin inhibitors. In particular, the invention relates to compounds of the formula I according 5 to Claim 1 and/or acceptable salts thereof in which R 2 has the meaning camphor-1 0-sulfonyl or 2,2-dimethylpropoxycarbonyl, for the preparation of a medicament for combating pathologically angiogenic diseases, tumours, osteoporosis, inflammation and infections. 10 The compounds of the formula I can be employed as medicament active ingredients in human and veterinary medicine, for the prophylaxis and/or therapy of thrombosis, myocardial infarction, arteriosclerosis, inflamma tion, apoplexy, angina pectoris, tumour diseases, osteolytic diseases, such as osteoporosis, pathologically angiogenic diseases, such as, for example, 15 inflammation, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatic arthritis, osteo arthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, athero sclerosis, psoriasis, restenosis after angioplasty, viral infection, bacterial infection, fungal infection, in the case of acute kidney failure and in wound 20 healing for supporting the healing processes. The compounds of the formula I can be employed as antimicrobially acting substances in operations where biomaterials, implants, catheters or car diac pacemakers are used. They have an antiseptic action here. The effi 25 cacy of the antimicrobial activity can be determined by the method described by P.Valentin-Weigund et al., in Infection and Immunity, 2851 2855 (1988). The abbreviations mentioned above and below stand for: 30 Ac acetyl Bn benzyl BOC tert-butoxycarbonyl CBZ or Z benzyloxycarbonyl 35 DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCCI dicyclohexylcarbodiimide WO 2004/072054 PCT/EP2004/000210 -14 DMF dimethylformamide DOPA (3,4-dihydroxyphenyl)alanine DPFN 3,5-dimethylpyrazol-1-formamidinium nitrate EDCI N-ethyl-N, N'-(dimethylaminopropyl)carbodiimide 5 Et ethyl Fmoc 9-fluorenylmethoxycarbonyl HOBt 1 -hydroxybenzotriazole Me methyl Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl 10 HONSu N-hydroxysuccinimide POA phenoxyacetyl TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetra fluoroborate TFA trifluoroacetic acid 15 Trt trityl (triphenylmethyl) Z or CBZ benzyloxycarbonyl. The compounds of the formula I is also taken to mean the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers 20 and the hydrates and solvates of these compounds. Solvates of the com pounds is taken to mean adductions of inert solvent molecules onto the compounds which form owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alcoholates. 25 Pharmaceutically usable derivatives is taken to mean, for example, the salts of the compounds according to the invention and also so-called pro drug compounds. Prodrug derivatives is taken to mean compounds of the formula I which have been modified with, for example, alkyl or acyl groups, sugars or 30 oligopeptides and which are rapidly cleaved in the organism to give the active compounds according to the invention. These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 115, 61-67 (1995). 35 WO 2004/072054 PCT/EP2004/000210 -15 The compounds of the formula I also encompass mixtures of the com pounds of the formula 1, for example mixtures of two diastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. These are particularly preferably mixtures of stereoisomeric compounds. 5 Throughout the invention, all radicals which occur a number of times, such as, for example, A and A', may be identical or different, i.e. are independ ent of one another. 10 In the above formulae, alkyl has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 C atoms and preferably stands for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also for pentyl, 1-, 2- or 3-methylbutyl, 1,1- , 1,2- or 2,2-dimethylpropyl, 1 -ethylpropyl, hexyl, 1- , 2-, 3- or 4-methylpentyl, 1,1- , 1,2-, 1,3- , 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 15 2-ethylbutyl, 1-ethyl-1 -methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-, 1,2,2 trimethylpropyl, heptyl, octyl, nonyl or decyl. In a preferred embodiment, A denotes unsubstituted alkyl or cycloalkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 C atoms. 20 Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclo hexyl, cycloheptyl or 3-menthyl. In particular, cycloalkyl denotes the radi cal of a bicyclic terpene, the camphor-1 0-yl radical is very particularly preferred. 25 Alkylene preferably denotes methylene, ethylene, propylene, butylene, pentylene, furthermore also hexylene, heptylene, ocytylene, nonylene or decylene. Aralkylene preferably denotes alkylenephenyl and is, for example, prefer ably benzyl or phenethyl. 30 Cycloalkylene preferably denotes cyclopropylene, 1,2- or 1,3-cyclobutyl ene, 1,2- or 1,3-cyclopentylene, 1,2-, 1,3- or 1,4-cyclohexylene, further more 1,2-, 1,3- or 1,4-cycloheptylene. 35 CO-A is alkanoyl or cycloalkanoyl and preferably denotes formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, WO 2004/072054 PCT/EP2004/000210 - 16 decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, penta decanoyl, hexadecanoyl, heptadecanoyl or octadecanoyl. Acyl is C-C 7 -acyl and has 1, 2, 3, 4, 5, 6 or 7 C atoms and preferably 5 denotes, for example, formyl, acetyl, propionyl, butyryl, trifluoroacetyl or benzoyl. Preferred substituents for alkyl, alkylene, cycloalkyl, cycloalkylene, alka noyl and cycloalkanoyl are, for example, Hal, OA, NHA, NA', CN, NO 2 , 10 SA, SOA, SO 2 A, SO 2 Ar and/or SO 3 H, in particular, for example, F, Cl, hydroxyl, methoxy, ethoxy, amino, dimethylamino, methylthio, methyl sulfinyl, methylsulfonyl or phenylsulfonyl. Preferred substituents for Ar and arylene are, for example, A and/or Hal, 15 OA, NHA, NAA', CN, NO 2 , SA, SOA, SO 2 A, SO 2 Ar and/or SO 3 H, in par ticular, for example, F, Cl, hydroxyl, methoxy, ethoxy, amino, dimethyl amino, methylthio, methylsulfinyl, methylsulfonyl or phenylsulfonyl. In the radicals alkyl, alkylene, cycloalkyl, cycloalkylene, alkanoyl and 20 cycloalkanoyl, in each case one, two or three methylene groups may be replaced by N, 0 and/or S. Ar-CO is aroyl and preferably denotes benzoyl or naphthoyl. 25 Ar is unsubstituted, preferably - as indicated - monosubstituted phenyl, in detail preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-cyanophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxy phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p 30 chlorophenyl, o-, m- or p-methylthiophenyl, o-, m- or p-methylsulfinyl phenyl, o-, m- or p-methylsulfonylphenyl, o-, m- or p-aminophenyl, o-, m or p-methylaminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- or p nitrophenyl, furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 35 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5 dibromophenyl, 2-chloro-3-methyl-, 2-chloro-4-methyl-, 2-chloro-5-methyl-, WO 2004/072054 PCT/EP2004/000210 -17 2-chloro-6-methyl-, 2-methyl-3-chloro-, 2-methyl-4-chloro-, 2-methyl-5 chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl- or 3-methyl-4-chlorophenyl, 2-bromo-3-methyl-, 2-bromo-4-methyl-, 2-bromo 5-methyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-, 2-methyl-4-bromo-, 5 2-methyl-5-bromo-, 2-methyl-6-bromo-, 3-bromo-4-methyl-, 3-bromo-5 methyl- or 3-methyl-4-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4 dimethoxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-tri-tert-butylphenyl, 2,5-dimethylphenyl, p-iodophenyl, 4-fluoro-3 chlorophenyl, 4-fluoro-3,5-dimethylphenyl, 2-fluoro-4-bromophenyl, 2,5 10 difluoro-4-bromophenyl, 2,4-dichloro-5-methylphenyl, 3-bromo-6-methoxy phenyl, 3-chloro-6-methoxyphenyl, 2-methoxy-5-methylphenyl, 2,4,6-tri isopropylphenyl, naphthyl, 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, benzothiadiazol-5-yl or benzoxadiazol-5-yl. Furthermore, Ar preferably denotes 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 15 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxa zolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-tri azol-1 -, -4- or -5-yl, 1,2,4-triazol-1 -, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3 oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5 20 yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4-H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5- 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benz 25 isoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothia zolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-qui nolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl. 30 Arylene has the same meanings as indicated for Ar, with the proviso that a further bond from the aromatic system to the closest bond neighbour has been formed. Heterocycloalkylene preferably denotes 1,2-, 2,3- or 1,3-pyrrolidinyl, 1,2-, 35 2,4-, 4,5- or 1,5-imidazolidinyl, 1,2-, 2,3-, or 1,3-pyrazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-oxazolidinyl, 1,2-, 2,3-, 3,4- or 1,4- isoxazolidinyl, 2,3-, 3,4-, WO 2004/072054 PCT/EP2004/000210 -18 4,5- or 2,5-thiazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-isothiazolidinyl, 1,2-, 2,3-, 3,4- or 1,4-piperidinyl, 1,4- or 1,2-piperazinyl, furthermore preferably 1,2,3 tetrahydrotriazol-1,2- or -1,4-yl, 1,2,4-tetrahydrotriazol-1,2- or 3,5-yl, 1,2 or 2,5-tetrahydrotetrazolyl, 1,2,3-tetrahydrooxadiazol-2,3-, -3,4-, -4,5- or 5 -1,5-yl, 1,2,4-tetrahydrooxadiazol-2,3-, -3,4- or -4,5-yl, 1,3,4-tetrahydro thiadiazol-2,3-, -3,4-, -4,5- or -1,5-yl, 1,2,4-tetrahydrothiadiazol-2,3-, -3,4-, -4,5- or -1,5-yl, 1,2,3-thiadiazol-2,3-, -3,4-, -4,5- or -1,5-yl, 2,3- or 3,4-mor pholinyl, 2,3-, 3,4- or 2,4-thiomorpholinyl. 10 R 6 is a mono- or bicyclic saturated, unsaturated or aromatic heterocycle, preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5 imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazoT lyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5 or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1 -, -4- or -5-yl, 1,2,4 15 triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4 oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5 yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4-H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5- 6- or 7 benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7 20 indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7 benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 25 8-quinazolinyl. The heterocyclic radicals may also be partially or fully hydrogenated. R can thus also denote, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4 yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5 30 dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1 -, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro 1-, -3- or -4-pyrazolyl, 1,4-dihydro-1 -, -2-, -3- or -4-pyridyl, 1,2,3,4-tetra hydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, 35 -4- or -5-yl, hexahydro-1 -, -3- or -4-pyridazinyl, hexahydro-1 -, -2-, -4- or -5 pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, WO 2004/072054 PCT/EP2004/000210 -19 -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1 -,-2-,-3-, -4-, -5-, -6-, -7- or -8 isoquinolyl. The said heterocyclic rings may also be mono-, di- or trisubstituted by Hal, 5 A, -CO-A, OA, CN, COOH, COOA, CONHA, NO 2 , =NH or =0.
R
6 particularly preferably denotes 1 H-imidazol-2-yl, thiazol-2-yi, 1 H-benz imidazol-2-yl, 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidin-4-on 5-yl, 1-A-1,5-dihydroimidazol-4-on-2-yl, pyrimidin-2-yl or 1,4,5,6-tetra 10 hydropyrimidin-2-yl, 1 H-imidazol-2-yl is very particularly preferred.
R
3 preferably denotes H.
R
4 preferably denotes H.
R
9 preferably denotes H. 15
R
1 0 preferably denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms, camphor 1 0-yl or benzyl. In the process according to the invention, in step b), in the compounds of 20 the formula IV and V,
R
8 preferably denotes methylsulfonyl, trifluoromethylsulfonyl, phenyl sulfonyl or p-tolylsulfonyl. Accordingly, the invention relates, in particular, to the processes for the 25 preparation of compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some pre ferred groups of compounds which are prepared by the process according to the invention can be expressed by the following sub-formulae la to If, which conform to the formula I and in which the radicals not designated in 30 greater detail have the meaning indicated for the formula I, but in which in Ia) R 3 denotes H and
R
4 denotes H; 35 in Ib) R 6 denotes 1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazol 2-yl, 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazol- WO 2004/072054 PCT/IEP2004/000210 -20 idin-4-on-5-yl, 1-A-1,5-dihydroimidazol-4-on-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl; in Ic) R 9 denotes H; 5 in Id) R 1 0 denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms, cam phor-10-yl or benzyl; in le) A denotes unsubstituted alkyl or cycloalkyl having 1-15 C 10 atoms; in If) A denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms,
R
1 0 denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms, cam phor-10-yl or benzyl, 15 and pharmaceutically usable derivatives, solvates and stereo isomers thereof. Preference is given to a process for the preparation of compounds of the formula I in which 20 R' denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or benzyl, R2 denotes R 1 0 , CO-R 1 0 , COOR 10 or S0 2 R'*,
R
3 denotes H,
R
4 denotes H, 25
R
5 denotes R , R denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, 0 and/or S atoms, which may be un substituted or mono-, di- or trisubstituted by Hal, A, -CO-A, OA, CN, COOH, COOA, CONHA, NO 2 , =NH or =0, 30 x denotes NH,
R
1 0 denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms, camphor-1 0-yI or benzyl, A denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms, Hal denotes F, CI, Br or I, 35 and pharmaceutically usable derivatives, solvates and stereoisomers thereof.
WO 2004/072054 PCT/EP2004/000210 -21 In the last-mentioned preferred embodiment, R 6 preferably denotes 1 H imidazol-2-yl, thiazol-2-yl, 1 H-benzimidazol-2-yl, 2H-pyrazol-2-yl, 1 H-tetra zol-5-yl, 2-iminoimidazolidin-4-on-5-yl, 1-A-1,5-dihydroimidazol-4-on-2-yl, 5 pyrimidin-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl. Preference is furthermore given to a process for the preparation of com pounds of the formula la 10 HR3 O OyR1 H HN R2 15R (CH2)2 R4 0 in which R1 denotes H or alkyl having 1, 2, 3 or 4 C atoms, R 2 denotes R 1 0 , CO-R 1 0 , COOR 10 or S0 2 R'*, 20 R 3 denotes H, R4 denotes H,
R
5 denotes R , X denotes NH,
R
6 denotes 1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazol-2-yl, 2H 25 pyrazol-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidin-4-on-5-yl, 1-A 1,5-dihydroimidazol-4-on-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydro pyrimidin-2-yl,
R
1 0 denotes H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and A denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms, 30 and pharmaceutically usable derivatives, solvates and stereoisomers thereof, where a) 5-oxotetrahydrofuran-2-carboxylic acid is reacted with a compound of the formula Il
R
7 -L I WO 2004/072054 PCT/EP2004/000210 - 22 in which
R
7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and L denotes Cl, Br, I or a free or reactively functionally modified OH 5 group, to give a compound of the formula Ill 0 0 10 R7 R7 OH in which 15 R 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, b) then a compound of the formula III is reacted with a compound of the formula IV Ra-L IV 20 in which Re 8 denotes alkylsulfonyl having 1-6 C atoms or arylsulfonyl having 6-10 C atoms and L denotes CI, Br, I or a free or reactively functionally modified OH 25 group, to give a compound of the formula V 30 0 0 30R7 1-O 07 1R7 ~~0 R8 35 in which
R
7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and WO 2004/072054 PCT/EP2004/000210 - 23 R 8 denotes alkylsulfonyl having 1-6 C atoms or arylsulfonyl having 6-10 C atoms, c) then a compound of the formula Ill or V is reacted with a compound 5 of the formula VI R3 0 10 02N ONR1 10 HO R 2 VI R4 in which 15 R1 denotes H or alkyl having 1, 2, 3 or 4 C atoms, R2 denotes R", CO-R", COOR 1 0 or SO 2
R'
0 , R 3 denotes H, R 4 denotes H, R1" denotes H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and, 20 to give a compound of the formula VII R3 0 25 R7 02N ON R'1 2 5 22 O HN OR2 O R4 Vil 30 0 R7 in which R1 denotes H or alkyl having 1, 2, 3 or 4 C atoms, 35 R2 denotes R 1 0 , CO-R 10 , COOR'" or S0 2
R
0 ,
R
3 denotes
H,
WO 2004/072054 PCT/EP2004/000210 - 24 R 4 denotes H, RT 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms,
R
1 0 denotes H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, 5 d) then a compound of the formula VII is converted into a compound of the formula Vill H ~ R 3 0 100 O y:' N -R1 10HO 2 2 H O HN R HO 0RR2Villi (CH 2)2 R 0 15 in which R1 denotes H or alkyl having 1, 2, 3 or 4 C atoms, R 2 denotes R1", CO-R10, COOR'0 or SO2R'*, R 3 denotes H, R 4 denotes H, 20 R10 denotes H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, e) then a compound of the formula Vill 25is reacted with a compound of the formula X R 6-NH2 X in which R6 denotes 1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazol-2-yl, 2H pyrazol-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidin-4-on-5-yl, 1-A 30 1,5-dihydroimidazol-4-on-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydro pyrimidin-2-yl, to give a compound of the formula la, 35 subsequently, if desired, a radical R 2 is converted into another radical R 2 WO 2004/072054 PCT/EP2004/000210 - 25 by reacting a compound of the formula la in which R 2 denotes H with a compound selected from the group
L-R'
0 ', L-CO-R'"', L-COOR'"', R'"'-SO 2 L, 5 in which
R
1 0 ' denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms and L denotes Cl, Br, I or a free or reactively functionally modified OH group, 10 and/or a base or acid of the formula la is converted into one of its salts. The invention furthermore relates to a process for the preparation of (S)-2 (2,2-dimethylpropoxycarbonylamino)-3-{(S)-2-[2-(1 H-imidazol-2-ylcarba moyl)ethyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}propionic acid, 15 where a) (S)-3-nitrotyrosine ethyl ester tosylate is reacted with 2,2-dimethyl propyl chloroformate to give ethyl (S)-2-(2,2-dimethylpropoxycarbonyl amino)-3-(4-hydroxy-3-nitrophenyl)propionate 12, 20 b) 12 is reacted with dibenzyl 2-hydroxypentanedicarboxylate to give dibenzyl (R)-2-{4-[(S)-2-(2,2-dimethylpropoxycarbonylamino)-2-ethoxy carbonylethyl]-2-nitrophenoxy}pentanedicarboxylate 13, 25 c) j3 is cyclised to give ethyl (2S)-3-[(2S)-2-(2-carboxyethyl)-3-oxo 3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-2-(2,2-dimethylpropoxycarbonyl amino)propionate 14, d) 14 is reacted with 2-aminoimidazole to give ethyl 2-(S)-(2,2 30 dimethylpropoxycarbonylamino)-3-{3-oxo-2-(S)-[2-(1 H-imidazol-2-yl carbamoyl)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}propionate 15 and e) 15 is converted by ester cleavage into (S)-2-(2,2-dimethylpropoxy carbonylamino)-3-{(S)-2-[2-(1 H-imidazol-2-ylcarbamoyl)ethyl]-3-oxo-3,4 dihydro-2H-benzo[1,4]oxazin-6-yl}propionic acid 16. 35 WO 2004/072054 PCT/EP2004/000210 -26 The term "amino-protecting group" is known in general terms and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical 5 of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), their type and size is furthermore not crucial; however, preference is given to those hav ing 1-20, in particular 1-8, C atoms. The term "acyl group" is to be under 10 stood in the broadest sense in connection with the present process. It en compasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxy carbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Exam ples of such acyl groups are alkanoyl, such as acetyl, propionyl, butyryl; 15 aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl or tolyl; aryloxy alkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxy carbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxy carbonyl, FMOC; arylsulfonyl, such as Mtr. Preferred amino-protecting 20 groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl. The amino-protecting group is cleaved off - depending on the protecting group used - for example using strong acids, advantageously using TFA or perchloric acid, but also using other strong inorganic acids, such as 25 hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such as benzene- or p-toluene sulfonic acid. The presence of an additional inert solvent is possible, but is not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydro 30 furan or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the above-mentioned solvents are furthermore suitable. TFA is preferably used in excess without addition of a further solvent, perchloric acid is preferably used in the form of a mixture 35 of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction tem- WO 2004/072054 PCT/EP2004/000210 - 27 peratures for the cleavage are advantageously between about 0 and about 500, preferably between 15 and 300 (room temperature). The BOC, OBut and Mtr groups can, for example, preferably be cleaved 5 off using TFA in dichloromethane or using approximately 3 to 5N HCI in dioxane at 15-30*, the FMOC group can be cleaved off using an approxi mately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30*. 10 Protecting groups which can be removed hydrogenolytically (for example CBZ or benzyl) can be cleaved off, for example, by treatment with hydro gen in the presence of a catalyst (for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon). Suitable sol vents here are those indicated above, in particular, for example, alcohols, 15 such as methanol or ethanol, or amides, such as DMF. The hydrogenoly sis is generally carried out at temperatures between about 0 and 1000 and pressures between about 1 and 200 bar, preferably at 20-30* and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydro 20 gen) on Pd/C in methanol/DMF at 20-30*. In the compounds of the formula 11, IV, and in the compounds selected from the groups
L-R
1 0 , L-CO-R 0 , L-COOR 6 , L-COOR 10 , R'"-N=C=O, R 6
-SO
2 L, R 1
*-SO
2 L 25 (step e) ii)) or L-R'O', L-CO-R' 1 , L-COOR 6 , L-COOR' 0 ', R 10 -N=C=O,
R
6
-SO
2 L, R 1
C-SO
2 L, L preferably denotes Cl, Br, I or a free or reactively modified OH group, such as alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyl oxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or 30 p-tolylsulfonyloxy). The reaction of 5-oxotetrahydrofuran-2-carboxylic acid with a compound of the formula il to give a compound of the formula Ill is generally carried out in an inert solvent, in the presence of an acid-binding agent, preferably an 35 organic base, such as triethylamine, dimethylaniline, pyridine or quinoline.
WO 2004/072054 PCT/EP2004/000210 - 28 The addition of an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium, calcium or caesium, may also be favourable. 5 Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature is between about -30* and 1400, normally between -100 and 900, in particular between about 00 and about 700. 10 Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloro form or dichloromethane; alcohols, such as methanol, ethanol, isopropa nol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, 15 diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon 20 disulfide; carboxylic acids, such as formic acid or acetic acid; nitro com pounds, such as nitromethane or nitrobenzene; esters, such as ethyl ace tate, water, or mixtures of the said solvents. The reaction of a compound of the formula Ill with a compound of the for 25 mula IV to give a compound of the formula V is generally carried out in an inert solvent, in the presence of an acid-binding agent, in an inert solvent and at temperatures as described for the reaction of 5-oxotetrahydrofuran 2-carboxylic acid with a compound of the formula 11. 30 If the further reaction is carried out by reaction of a compound of the for mula V with a compound of the formula VI to give a compound of the for mula VII, this reaction is generally carried out in an inert solvent, in the presence of an acid-binding agent, in an inert solvent and at temperatures as described for the reaction of 5-oxotetrahydrofuran-2-carboxylic acid 35 with a compound of the formula 11.
WO 2004/072054 PCT/EP2004/000210 -29 If, alternatively, the further reaction is carried out by reaction of a com pound of the formula Ill with a compound of the formula VI to give a com pound of the formula VII, this is carried out under conditions of the Mitsu nobu reaction, which are known to the person skilled in the art for this 5 reaction. The conversion of a compound of the formula Vil into a compound of the formula Vill is carried out, if R 7 denotes benzyl, preferably hydrogenolyti cally under conditions as described above. The reduction of the nitro 10 group and the cleaving-off of the benzyl groups with cyclisation take place here. Alternatively, the conversion of a compound of the formula VIl into a com pound of the formula Vill is carried out 15 a) by reduction of the nitro group, subsequent ester cleavage and cyclisation or b) by ester cleavage, subsequent reduction of the nitro group and cyclisation. 20 An ester cleavage takes place under standard conditions. This is advanta geously carried out by solvolysis or hydrogenolysis, as indicated above, for example using NaOH or KOH in dioxane/water at temperatures between 0 and 60 0 C, preferably between 10 and 40 0 C. 25 The reaction of a compound of the formula Vill or Villa with a compound of the formula IX or X to give a compound of the formula I is generally carried out in an inert solvent, in the presence of an acid-binding agent, in an inert solvent and at temperatures as described for the reaction of 5-oxotetra hydrofuran-2-carboxylic acid with a compound of the formula 11. 30 In the compounds of the formula Villa, L preferably denotes Cl, Br, I or a reactively modified OH group, such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferably methyl sulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 C 35 atoms (preferably phenyl- or p-tolylsulfonyloxy).
WO 2004/072054 PCT/EP2004/000210 -30 Radicals of this type for activation of the carboxyl group in typical acylation reactions are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart;). 5 Activated esters are advantageously formed in situ, for example by addi tion of HOBt or N-hydroxysuccinimide. If desired, a radical R2 in a compound of the formula I is converted into another radical R 2 . This is preferably carried out with compounds of the 10 formula I in which R 2 denotes H. The reaction is carried out with a com pound selected from the group L-R'*, L-CO-R'*, L-COOR 6 , L-COOR' , R'"-N=C=O, R -SO 2 L,
R'
0
-SO
2 L 15 in which
R
1 0 denotes A, Ar or aralkylene having 7-14 C atoms, A and Ar have the meanings indicated in Claim 1 and L denotes Cl, Br, I or a free or reactively functionally modified OH group. The reaction is generally carried out in an inert solvent, in the presence of 20 an acid-binding agent, in an inert solvent and at temperatures as described for the reaction of 5-oxotetrahydrofuran-2-carboxylic acid with a compound of the formula 11. The conversion of a cyano group into an amidino group is carried out by 25 reaction with, for example, hydroxylamine and subsequent reduction of the N-hydroxyamidine using hydrogen in the presence of a catalyst, such as, for example, Pd/C. A base of the formula I can be converted into the associated acid-addition 30 salt using an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as ethanol, followed by evapo ration. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric 35 acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, WO 2004/072054 PCT/EP2004/000210 -31 araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfo nic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, 5 gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids, laurylsulfuric acid. Salts with physiologically unaccept able acids, for example picrates, can be used for the isolation and/or puri 10 fication of the compounds of the formula 1. On the other hand, an acid of the formula I can be converted into one of its physiologically acceptable metal or ammonium salts by reaction with a base. Possible salts here are, in particular, the sodium, potassium, magne 15 sium, calcium and ammonium salts, furthermore substituted ammonium salts, for example the dimethyl-, diethyl- or diisopropylammonium salts, monoethanol-, diethanol- or diisopropylammonium salts, cyclohexyl-, dicyclohexylammonium salts, dibenzylethylenediammonium salts, further more, for example, salts with arginine or lysine. 20 The compounds of the formula I contain one or more chiral centres and can therefore exist in racemic or optically active form. The racemates obtained can be resolved into the enantiomers mechanically or chemically by methods known per se. Diastereomers are preferably formed from the 25 racemic mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids, such as p-camphorsulfonic acid. Also advanta 30 geous is enantiomer resolution with the aid of a column filled with an opti cally active resolving agent (for example dinitrobenzoylphenylglycine); an example of a suitable eluent is a hexane/isopropanol/acetonitrile mixture, for example in the volume ratio 82:15:3. 35 WO 2004/072054 PCT/EP2004/000210 - 32 It is of course also possible to obtain optically active compounds of the formula I by the methods described above by using starting materials which are already optically active. 5 The invention furthermore relates to the intermediate compounds of the formula VII R3 O 10 R7 02 NNO0111R1 102a 0 IHN O R4 Vil 15 0 R7 in which R1 denotes H or alkyl having 1, 2, 3 or 4 C atoms, 20 R2 denotes R 1 0 , CO-R 1 0 , COOR 10 or SO 2 R'*,
R
3 denotes H,
R
4 denotes H,
R
7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, R' 9 denotes H, Hal, OA, NHA, NAA', NHacyl, Oacyl, CN, NO 2 , SA, 25 SOA, SO 2 A, SO 2 Ph or SO 3 H,
R'
0 denotes H, A, Ar or aralkylene having 7-14 C atoms, A, A' each, independently of one another, denote H or alkyl or cycloalkyl having 1-15 C atoms, each of which is unsubstituted or mono-, di or trisubstituted by R 9 and in which one, two or three methylene 30 groups may be replaced by N, 0 and/or S, Ar denotes mono- or bicyclic aromatic ring system having 0, 1, 2, 3, or 4 N, 0 and/or S atoms, which is unsubstituted or mono-, di- or trisubstituted by A and/or R 9 , and salts, solvates and stereoisomers thereof. 35 WO 2004/072054 PCTIEP2004/000210 - 33 Preference is furthermore given to the intermediate compounds of the for mula VII R3 0 5 R02N 0R1 O HN R O ) R4 10 Vil o 0 R7 in which 15 R1 denotes H or alkyl having 1, 2, 3 or 4 C atoms, R 2 denotes R", CO-R'", COOR'O or S0 2 R'", R3 denotes H, R 4 denotes H, RT 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, 20 R 1 0 denotes H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, and salts, solvates and stereoisomers thereof. In addition, the invention relates to a process for the preparation of com pounds of the formula VII, 25 and salts, solvates and stereoisomers thereof, in which a) 5-oxotetrahydrofuran-2-carboxylic acid is reacted with a compound of the formula 11 30 R 7 -L 11 where RT 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and L denotes Cl, Br, I or a free or reactively functionally modified OH 35 group, WO 2004/072054 PCT/EP20041000210 -34 to give a compound of the formula Ill 0 0 5 R7O 0 7 OH in which RT denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, 10 b) then a compound of the formula Ill is reacted with a com pound of the formula IV R-L IV 15 in which
R
8 denotes alkylsulfonyl having 1-6 C atoms or arylsulfonyl having 6-10 C atoms and L denotes Cl, Br, I or a free or reactively functionally modified OH group, 20 to give a compound of the formula V 0 0 25 R7 VO 0" R7 R8 in which 30 R 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and
R
8 denotes alkylsulfonyl having 1-6 C atoms or arylsulfonyl having 6-10 C atoms, c) then a compound of the formula Ill or V is reacted with a compound of the formula VI WO 2004/072054 PCT/EP2004/000210 - 35 R3 0 0 2 N R1 5 HO R2 VI R4 in which R1 denotes H or alkyl having 1, 2, 3 or 4 C atoms, 10 R2 denotes RO, CO-R', COOR 10 or S0 2
R
0 ,
R
3 denotes H, R 4 denotes H,
R
9 denotes H, Hal, OA, NHA, NAA', NHacyl, Oacyl, CN, NO 2 , SA, SOA, SO 2 A, SO 2 Ph or SO 3 H, 15 R 1 0 denotes H, A, Ar or aralkylene having 7-14 C atoms, A, A' each, independently of one another, denote H or alkyl or cycloalkyl having 1-15 C atoms, each of which is unsubstituted or mono-, di or trisubstituted by R 9 and in which one, two or three methylene groups may be replaced by N, 0 and/or S, 20 Ar denotes mono- or bicyclic aromatic ring system having 0, 1, 2, 3 or 4 N, 0 and/or S atoms which is unsubstituted or mono-, di- or tri substituted by A and/or R 9 , to give a compound of the formula VII, 25 and/or an acid of the formula VII is converted into one of its salts. The reactions are carried out analogously to the conditions as described for the preparation of the compounds of the formula I. 30 Above and below, all temperatures are indicated in *C. In the following examples, "conventional work-up" means: if necessary, water is added, the pH is set to values between 2 and 10, depending on the constitution of the 35 end product, are set, if necessary, the mixture is extracted with ethyl ace tate or dichloromethane, the phases are separated, the organic phase is WO 2004/072054 PCT/EP2004/000210 - 36 dried over sodium sulfate and evaporated, and the product is purified by chromatography on silica gel and/or by crystallisation. Mass spectrometry (MS): El (electron impact ionisation) M* 5 FAB (fast atom bombardment) (M+H)* 10 15 20 25 30 35 WO 2004/072054 PCT/EP2004/000210 - 37 Example 1 The preparation of ethyl 2-(S)-amino-3-{3-oxo-2-(R)-[2-(1H-imidazol-2-yl carbamoyl)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}propionate hydro 5 chloride (6) is carried out analogously to the following scheme: Bn-O O-Bn O OH OH 101 10 0 0111 ON Bn-o +-B OH2) 0 OO 15 2 0 2 N 0 o 20 0 25 HD0-Et OZO HO 25 Boc 00 0 H-C NN O 35 00 6 WO 2004/072054 PCT/EP2004/000210 - 38 1.1 Dibenzyl (S)-2-hydroxypentanedicarboxylate 1 300 g of caesium carbonate are added to a solution of 100 g of (S)-5-oxo furan-2-carboxylic acid in 1 I of water. The mixture is heated under reflux 5 and stirred for 18 hours. The water is removed, and the residue is dis solved in 750 ml of methanol. 200 g of silica gel are added, and the mix ture is stirred for 15 minutes. The solvent is removed, giving the bis caesium salt on silica gel as a white powder, which is dried for 18 hours at 600 under reduced pressure. 10 The crude product is suspended in 1 1 of absolute DMF, 183 ml of benzyl bromide are added, and the mixture is stirred at room temperature for 16 hours. When the reaction is complete (HPLC check), the silica gel is separated off by filtration, and the solution is poured into 2 1 of water. Conventional 15 work-up gives I as oil. Yield: 237 g (94%) HPLC (Chromolith TM Performance RP-1 8e, eluent: gradient system, water + 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 -+ 1:99 in 10 min, 3 ml/min) Ri = 5.25 min 20 Chiral HPLC (Chiralcel OD-H, 250 mm, heptane/ethanol 85:15, 0.8 ml/min): Rt = 12.95 min ESI-MS: M- 1 = 329 1 H-NMR (400 MHz, DMSO): corresponds [a]D = - 9
.
6 * (c = 1.1 in ethanol). 25 1.2 Dibenzyl (S)-2-methanesulfonyloxypentanedicarboxylate 2 500 ml of triethylamine are added to a solution of 236.9 g of 1 in 1.2 | of dichloromethane. With ice cooling, a solution of 83.6 ml of methane 30 sulfonyl chloride in 200 ml of dichloromethane is added. The mixture is stirred at 5 - 100 for 30 minutes, the precipitated triethylamine hydro chloride is removed, and the product is subjected to conventional work-up, giving 2 as oil. 35 Yield: 277 g (94%) WO 2004/072054 PCT/EP2004/000210 - 39 HPLC (Chromolith T M Performance RP-1 8e, eluent gradient system: water + 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 - 1:99 in 10 min, 3 ml/min) Rt = 5.92 min DC: Si-60, toluene/acetone 9:1, Rf = 0.5 5 ESI-MS: M" = 407 [a]D = -31.1* (c = 1.01 in chloroform). 1.3 Dibenzyl 2-(R)-[4-(2-(S)-tert-butoxycarbonylamino-2-ethoxy carbonylethy)-2-nitrophenoxy]pentanedicarboxylate 3 10 174.1 g of potassium carbonate are added to a solution of 178.6 g of N-Boc-L-tyrosine ethyl ester and 257 g of 2 in 1.25 I of acetonitrile, and the mixture is heated under reflux for 16 hours. After the insoluble salts have been separated off, the mixture is subjected to conventional work-up, 15 giving 3. Yield: 369 g (99%) HPLC (Chromolith TM Performance RP-1 8e, eluent gradient system: water + 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 - 1:99 in 10 min, 3 ml/min) 20 Rt = 7.04 min, purity 90%. Chiral HPLC: (Chiralpak m AD, 250 mm, heptane/isopropanol 60:40, 0.8 ml/min) Ri = 27.23 min, purity = 96.6% (de [diastereomeric excess] = 93.2%) DC: Si-60, toluene/acetone 9:1, Rf = 0.38 25 ESI-MS: M'' = 665 [a]D = -35.8* (c = 1.02 in ethanol). 1.4 Ethyl 2-(S)-tert-butoxycarbonylamino-3-[2-(R)-(2-carboxyethyl)-3 oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]propionate 4 30 Hydrogen is passed through a solution of 369 g of 3 in 2.6 I of acetic acid at 600 in the presence of 95 g of palladium (5% on activated carbon) for 6 hours. Removal of the catalyst and conventional work-up gives 4. Yield: 164 g (75%) 35 WO 2004/072054 PCT/EP2004/000210 -40 HPLC (Chromolith TM Performance RP-1 8e, eluent gradient system: water + 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 + 1:99 in 10 min, 3 ml/min) Rt= 4.51 min. DC: Si-60, dichloromethane/methanol 9:1, Rf 0.35 5 ESI-MS: M' = 437 [a]D = +14.0* (c = 1.0 in methanol) m.p. 154 - 158*. 1.5 Ethyl 2-(S)-tert-butoxycarbonylamino-3-{3-oxo-2-(R)-[2-(1 H-imida 10 zol-2-ylcarbamoyl)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}propionate 5 128.54 g of potassium carbonate are added to a solution of 163 g of 4, 74 g of 2-aminoimidazole sulfate, 155.7 g of TBTU and 15.13 g of HOBt in 15 1.2 I of absolute DMF, and the mixture is stirred at 700 under nitrogen for 16 hours. A further 25 g of 2-aminoimidazole sulfate, 51 g of TBTU, 5 g of HOBt and 26 g of potassium carbonate are added, and the mixture is stirred for a further 5 hours. The insoluble salts are separated off, the DMF is removed, and the residue is poured into 3 1 of ice-water. The precipitate 20 is separated off, washed with water and dried in air. Recrystallisation from ethanol gives 5. Yield: 125 g (67%) HPLC (ChromolithTM Performance RP-1 8e, eluent gradient system: water + 25 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 -+ 1:99 in 10 min, 3 ml/min) Rt = 4.13 min. Chiral HPLC: (Chiralpaki" AD, 250 mm, heptane/ethanol 40:60, 0.8 ml/min) Rt = 16.21 min, purity = 96.6% (de = 93.2%) DC: Si-60, dichloromethane/methanol 9:1, Rf = 0.28 30 ESI-MS: M' = 502 [a]D = +17.3* (c = 1.04 in DMSO) m.p. 215 0 C (decomposition). 35 WO 2004/072054 PCT/EP2004/000210 -41 1.6 Ethyl 2-(S)-amino-3-{3-oxo-2-(R)-[2-(IH-imidazol-2-ylcarbamoyl) ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}propionate, hydrochloride 6 0.9 1 of a 4.5 M solution of HCI in dioxane is added to a suspension of 5 112 g of 5 in 1 1 of dioxane, and the mixture is stirred for a further 16 hours. The precipitate is separated off, washed with a little dioxane and 3x with petroleum ether. Drying under reduced pressure gives 6 as white product. 10 Yield: 112.6 g (quant.) HPLC (Chromolith TM Performance RP-18e, eluent gradient system: water + 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 - 1:99 in 10 min, 3 ml/min) Ri = 2.67 min. ESI-MS: M+ 1 = 402 15 m.p. 2200 (decomposition) [aID = +34.10 (c = 1.0 in water). Analogous reaction of 20 ethyl 2-(S)-tert-butoxycarbonylamino-3-[2-(R)-(2-carboxyethyl)-3-oxo 3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]propionate 4 with 25 2-aminobenzimidazole gives the compound ethyl 2-(S)-tert-butoxycarbonylamino-3-{3-oxo-2-(R)-[2-(1 H-benz 30 imidazol-2-ylcarbamoyl)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl} propionate 5-a. 35 WO 2004/072054 PCT/EP2004/000210 -42 Example 2 The preparation of (S)-2-(2,2-dimethylpropoxycarbonylamino)-3-{(R)-2-[2 (1 H-imidazol-2-ylcarbamoyl)ethyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin 5 6-yl}propionic acid, sodium salt (11) is carried out analogously to the fol lowing scheme: 0 0 0 10 Bn-O O-H + O2N 102 O.02HHO010 HNYO0 7 0 ONO O 2N
O--
15 HN O Bn-O O( O 0 O-Bn 0 20 H 0 N I Nk0 -E t HO, X 0- C0H N,0 25 0 0 H Y^X HN 0_1 30 N 0_ 0 H o N H ONa N IN YXo HN Y 35 0 Y0 WO 2004/072054 PCT/EP2004/000210 -43 2.1 Ethyl (S)-2-(2,2-dimethylpropoxycarbonylamino)-3-(4-hydroxy- 3 nitrophenyl)propionate 7 81.32 g of NaHCO 3 are added in small portions to a suspension of 206.4 g 5 of L-3-nitrotyrosine ethyl ester tosylate in 750 ml of water and 250 ml of THF. A solution of 60 ml of 2,2-dimethylpropyl chloroformate in 250 ml of THF is subsequently added dropwise, and the mixture is stirred at room temperature for a further 2 hours. After removal of the THF, the mixture is subjected to conventional work-up. The crystallised product 7 is washed 10 with petroleum ether and dried under reduced pressure. Yield: 107 g (72%) HPLC (Chromolith T M Performance RP-1 8e, eluent gradient system: water + 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 - 1:99 in 10 min, 3 ml/min) 15 Rt = 5.68 min. DC: Si-60, toluene/acetone 9:1, Rf = 0.42 ESI-MS: M+ 1 = 369 [a]D = +0.90 (c = 1.03 in methanol) m.p. 64-67*. 20 2.2 Dibenzyl (S) 2-{4-[(S)-2-(2,2-dimethylpropoxycarbonylamino)-2 ethoxycarbonylethyl]-2-nitrophenoxy}pentanedicarboxylate 8 9.24 g of K 2 C0 3 are added to a solution of 9.85 g of 7 in 100 ml of aceto 25 nitrile. A solution of 16.3 g of the mesylate 2 in 50 ml of acetonitrile is then added dropwise, and the mixture is stirred under reflux (bath temperature 80*) for 16 hours. The mixture is cooled to room temperature, the insoluble salts are separ ated off, the solvent is removed, the residue is dissolved in 200 ml of ethyl 30 acetate and subjected to conventional work-up, giving 8 as yellow syrup. Yield: 23 g (75% purity, still contains mesylate) HPLC (ChromolithTM Performance RP-18e, eluent gradient system: water + 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 - 1:99 in 10 min, 3 ml/min) 35 R= 7.17 min.
WO 2004/072054 PCT/IEP2004/000210 -44 Chiral HPLC: (ChiralpakTM AD, 250 mm, heptane/isopropanol 60:40, 0.8 mI/min) Rt = 22.35 min, diastereomeric purity = 98% (de = 96%) DC: Si-60, toluene/acetone 9:1, Rf = 0.38 ESI-MS: M'' = 679 5 [a]D = -36.9* (c = 1 in ethanol) 2.3 Ethyl (S)-3-[(R)-2-(2-carboxyethyl)-3-oxo-3,4-dihydro-2H-benzo [1,4]oxazin-6-yl]-2-(2,2-dimethylpropoxycarbonylamino)propionate 9 10 Hydrogen is passed through a solution of 23 g of 8 (crude product from 2.2) in 230 ml of acetic acid at 600 in the presence of 7.5 g of palladium (10% on activated carbon) for 6 hours. Removal of the catalyst and con ventional work-up and recrystallisation from ethanol gives 9. 15 Yield: 10 g (87%) HPLC (Chromolith T M Performance RP-18e, eluent gradient system: water + 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 + 1:99 in 10 min, 3 ml/min) Rt = 4.88 min. DC: Si-60, dichloromethane/methanol 9:1, Rf = 0.42 20 ESI-MS: M' 1 = 451 [(a]D = +9.6* (c = 1 in methanol) m.p. 99-1020. 2.4 Ethyl 2-(S)-(2,2-dimethylpropoxycarbonylamino)-3-{3-oxo-2-(R)-[2 25 (1 H-imidazol-2-ylcarbamoyl)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl} propionate 10 4.6 g of potassium carbonate are added to a solution of 10 g of 9, 4.4 g of 2-aminoimidazole sulfate, 9.26 g of TBTU and 0.9 g of HOBt in 100 ml of 30 absolute DMF, and the mixture is stirred at 70* under nitrogen for 16 hours. The mixture is cooled to room temperature, poured into 750 ml of cold water, the precipitate is separated off, washed with cold water and dried. The crude product is treated with hot acetonitrile and filtered off after cooling. The residue is recrystallised from ethanol, giving 10. 35 Yield: 8.5 g (74%) WO 2004/072054 PCT/IEP2004/000210 -45 HPLC (ChromolithTM Performance RP-1 Be, eluent gradient system: water + 0.1% of TFA/acetonitrile + 0.1% of TFA99:1 -1 1:99 in 10 min, 3 ml/min) Rt = 4.48 min. Chiral HPLC: (Chiralpak T M AD, 250 mm, heptane/ethanol 40:60, 5 0.8 ml/min) Rt = 21.95 min, diastereomeric purity = 99% (de = 98%) DC: Si-60, dichloromethane/methanol 9:1, Rf = 0.35 ESI-MS: M' 1 = 516 m.p. 2100C (decomposition) 10 2.5 (S)-2-(2,2-Dimethylpropoxycarbonylamino)-3-{(R)-2-[2-(1 H-imida zol-2-ylcarbamoyl)ethyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl} propionic acid, sodium salt 11 13.6 ml of 2N NaOH are added to a solution of 7 g of 10 in 70 ml of diox 15 ane, and the mixture is stirred at room temperature for a further 16 hours. The mixture is neutralised using dilute HCI, the dioxane is removed under reduced pressure, diluted with water, acidified, and the precipitate is sepa rated off and washed with water. Drying gives 11 as free acid. Yield: 5.1 g (77%). 20 For the preparation of the sodium salt, the product is dissolved in one equivalent (10.46 ml) of IN NaOH and subsequently lyophilised. Yield: 5.3 g 25 HPLC (Chromolith TM Performance RP-18e, eluent gradient system: water + 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 -+ 1:99 in 10 min, 3 ml/min) Rt = 3.79 min. Resolution of the diastereomers: LiChroSorb RP-1 8, 250/4 mm, eluent: 0.05 M (NH 4
)H
2
PO
4 buffer pH 4.0/acetonitrile 82/18, 0.8 ml/min, 30 Rt = 36.7 min ESI-MS: M' 1 = 488 [a]o = +18* (c = 1 in DMSO) m.p. 1850 (decomposition). 35 WO 2004/072054 PCT/EP2004/000210 -46 Example 3 The preparation of (S)-2-(2,2-dimethylpropoxycarbonylamino)-3-{(S)-2-[2 (1 H-imidazol-2-ylcarbamoyl)ethyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin 5 6-yllpropionic acid (16) is carried out analogously to the following scheme via Mitunobu reaction: 0 10 Bn-O ' O-Bn HHN OH 0 15 BnO-O 3-Et Bn-O O N 04 20 0 H 0 N 0-Et 1 HO0 H N Y01 0 4 25 0 H H O-E 3 15 30 H 0 H 35 IC ryD~o DA H NY 016 35 0 4 WO 2004/072054 PCT/EP2004/000210 - 47 3.1 Ethyl (S)-2-(2,2-dimethylpropoxycarbonylamino)-3-(4-hydroxy-3 nitrophenyl)propionate 12 81.3 g of NaHCO 3 are added in small portions to a solution of 206.4 g of 5 (S)-3-nitrotyrosine ethyl ester tosylate in 750 of water and 250 ml of THF. A solution of 60 ml of 2,2-dimethylpropyl chloroformate (neopentyl chloro formate) in 250 ml of THF is then slowly added dropwise, and the mixture is stirred at room temperature for a further 2 hours. After removal of the solvent, the mixture is subjected to conventional work-up, giving 12. 10 Yield: 107 g (72%) HPLC (Chromolith TM Performance RP-18e, eluent gradient system: water 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 -+ 1:99 in 10 min, 3 ml/min) Rt = 5.68 min. 15 DC: Si-60, toluene/acetone 9:1, Rf = 0.42 ESI-MS: M+' = 369 m.p. 64-67* [a]D = +0.9" (c = 1 in methanol). 20 3.2 Dibenzyl (R)-2-{4-[(S)-2-(2,2-dimethylpropoxycarbonylamino)-2 ethoxycarbonylethyl]-2-nitrophenoxy}pentanedicarboxylate 13 5.43 g of polymer-bound DEAD (diethyl azodicarboxylate) in 30 ml of THF are added to a solution of 4 g of 12 and 5.35 g of dibenzyl 2-hydroxy 25 pentanedicarboxylate (X) in anhydrous THF. The mixture is shaken for 16 hours. The polymer is separated off, and the solvent is removed. The resi due is taken up in ethyl acetate, and conventional work-up gives 13, which is not purified further for the further reaction. 30 Yield: 8.9 g (80% purity), colourless syrup; HPLC (ChromolithTM Performance RP-18e, eluent gradient system: water + 0.1% of TFAlacetonitrile + 0.1% of TFA 99:1 -o 1:99 in 10 min, 3 ml/min) Rt = 7.23 min. Chiral HPLC: (Chiralpak AD, 250 mm, heptane/isopropanol 60:40, 35 0.8 ml/min) Rt = 19.25 min, diastereomeric purity = 99% DC: Si-60, toluene/acetone 9:1, Rf = 0.38 WO 2004/072054 PCT/EP2004/000210 -48 ESI-MS: M*' = 679. 3.3 Ethyl (2S)-3-[(2S)-2-(2-carboxyethyl)-3-oxo-3,4-dihydro-2H-benzo [1,4]oxazin-6-yl]-2-(2,2-dimethylpropoxycarbonylamino)propionate 14 5 Hydrogen is passed through a solution of 8.4 g of 13 (crude product from 3.3) in 80 ml of acetic acid at 600 in the presence of 2.5 g of palladium (10% on activated carbon) for 5 hours. After removal of the catalyst, 15 g of zinc powder are added, and the mixture is stirred at 600 for a further one 10 1 hour. The mixture is filtered through silica gel, the solvent is removed, the residue is taken up in ethyl acetate, the solution is subjected to con ventional work-up, giving amorphous 14. Yield: 3.8 g (85%) 15 HPLC (Chromolith TM Performance RP-1 8e, eluent gradient system: water + 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 + 1:99 in 10 min, 3 ml/min) Rt = 4.83 min. DC: Si-60, dichloromethane/methanol 9:1, Rf = 0.42 ESI-MS: M' 1 = 451 20 3.4 Ethyl 2-(S)-(2,2-dimethylpropoxycarbonylamino)-3-{3-oxo-2-(S)-[2 (1 H-imidazol-2-ylcarbamoyl)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl} propionate 15 25 3.2 g of 14 are reacted with 1.88 g of 2-aminoimidazole, 2.96 g of TBTU, 0.29 g of HOBt and 2.95 g of potassium carbonate in 40 ml of DMF analo gously to the preparation of 5. Conventional work-up gives 15. Yield: 2.4 g (66%) 30 HPLC (ChromolithTM Performance RP-1 8e, eluent gradient system: water + 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 -+ 1:99 in 10 min, 3 mI/min) Rt = 4.40 min. Chiral HPLC: (Chiralpak AD, 250 mm, heptane/ethanol 40:60, 0.8 ml/min) Ri = 28.0 min, diastereomeric purity = 99% 35 DC: Si-60, dichloromethane/methanol 9:1, Rf = 0.33 ESI-MS: M' 1 = 516.
WO 2004/072054 PCT/IEP2004/000210 -49 3.5 (S)-2-(2,2-Dimethylpropoxycarbonylamino)-3-{(S)-2-[2-(1 H-imida zol-2-ylcarbamoyl)ethyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl} propionic acid 16 5 The ester cleavage of 2 g of 15 is carried out analogously to the prepara tion of 10. Yield: 1.7 g (90%) 10 HPLC (Chromolith TM Performance RP-18e, eluent gradient system: water + 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 -+ 1:99 in 10 min, 3 ml/min) Rt = 3.68 min. Resolution of the diastereomers: LiChroSorb m RP-1 8, 250/4 mm, eluent: 0.05 M (NH 4
)H
2
PO
4 buffer pH 4.0/acetonitrile 82/18, 0.8 ml/min, Rt = 33.07 15 min ESI-MS: M* 1 = 488. 20 25 30 35 WO 2004/072054 PCT/EP2004/000210 - 50 Example 4 (Comparative experiment) The preparation of tert-butyl 2-(S)-(2,2-dimethylpropoxycarbonylamino)-3 [2-(2-carboxyethyl )-3-oxo-3,4-dihydro-2H-benzo[1, 4]oxazin-6-yl]propionate 5 20 analogously to WO 98/35949 (Example 11): 0 0 Bn-O OH D-glutamic acid 10 NH2 1 0 BnO00OH
H
2 N IO.;: 15 Bn-O HHNH2N Br H 17 121 H 0 20 0 N 0B O-u Bn-O H " ' Br HO Y 18y oO 25H0 30 1 NyO 30 H 0 N HO 04N -Bu 20 35 0 WO 20041072054 PCT/EP2004/000210 - 51 4.1 5-Benzyl 2-bromopentanedicarboxylate 17 50 g of sodium nitrite are added in portions at 0-5* to a solution of 115 g of 5 5-benzyl D-glutamate and 190 g of KBr in 1.4 1 of 2.5N sulfuric acid, and the mixture is stirred for a further 1 hour, later at room temperature for a further 1 hour. Conventional work-up gives 17. Yield: 101.6 g (70%) 10 HPLC (Chromolith TM Performance RP-18e, eluent gradient system: water + 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 -o 1:99 in 10 min, 3 ml/min) Rt= 4.91 min. ESI-MS: M+' = 302. 15 4.2 Benzyl (S)-4-bromo-4-{5-[(S)-2-(2,2-dimethylpropoxycarbonyl amino)-2-tert-butyloxycarbonylethyl]-2-hydroxyphenylcarbamoyl}butyrate 18 66.3 g of EDCI hydrochloride are added in portions to a solution of 106 g 20 of tert-butyl (S)-2-(2,2-dimethylpropoxycarbonylamino)-2-(3-amino-4 hydroxyphenyl)propionate (12, obtainable from the corresponding 3-nitro derivative by reduction using H 2 /Pd,C) and 101 g of 17 in 1 I of absolute THF, and the mixture is stirred for a further 16 hours. The THF is removed, the residue is taken up in ethyl acetate, and the solution is subjected to 25 conventional work-up, giving 18 as yellow syrup, which is used for the further reaction without further purification. Yield: 216 g (85% purity, 98%) HPLC (Chromolith Performance RP-1 8e, eluent gradient system: water + 30 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 -+ 1:99 in 10 min, 3 mIl/min) Rt = 7.07 min. DC: Si-60, toluene/acetone 4:1, Rf = 0.41 ESI-MS: M' 1 = 650. 35 WO 2004/072054 PCT/EP2004/000210 - 52 4.3 tert-Butyl (S)-3-[2-(2-benzyloxycarbonylethyl)-3-oxo-3,4-dihydro 2H-benzo[1,4]oxazin-6-yl]-2-(2,2-dimethylpropoxycarbonylam ino)propion ate 19 5 43.14 of DBU are added to a solution of 215 g of 18 in 1250 ml of toluene, and the mixture is stirred at room temperature for a further one hour. The solvent is removed, and the residue is purified by flash chromatography over silica gel (eluent toluene/acetone gradient 20:1 - 4:1). Chiral HPLC shows a diastereomeric ratio of 2:1 of the R/S and S/S con 10 figured benzoxazinone derivatives. Yield: 69 g (43%) HPLC (Chromolith TM Performance RP-18e, eluent gradient system: water + 0.1% of TFA/acetonitrile + 0.1% of TFA99:1 -+ 1:99 in 10 min, 3 ml/min) 15 Rt = 7.01 min. Chiral HPLC: (Chiralpak T M AD, 250 mm, ethanol, 0.8 ml/min) Rt = 12.88 min, diastereomeric purity = 61% (de = 22%) DC: Si-60, toluene/acetone 4:1, Rf = 0.27 ESI-MS: M' 1 = 569. 20 4.4 tert-Butyl 2-(S)-(2,2-dimethylpropoxycarbonylamino)-3-[2-(2-car boxyethyl)-3-oxo-3,4-dihydro-2H-benzo[ 1,4]oxazin-6-yl]propionate 20 Hydrogen is passed through a solution of 26 g of 13 in 250 ml of THF at 25 room temperature in the presence of 6.5 g of palladium (10% on activated carbon) for 6 hours. The catalyst is separated off, the solvent is removed, and the residue is dried under reduced pressure. Yield: 21.5 g (98%) of amorphous foam 30 HPLC (Chromolith Performance RP-18e, eluent gradient system: water + 0.1% of TFA/acetonitrile + 0.1% of TFA 99:1 + 1:99 in 10 min, 3 ml/min) Rt = 5.63 min. DC: Si-60, dichloromethane/methanol 9:1, Rf= 0.44 ESI-MS: M' 1 = 479. 35 WO 2004/072054 PCT/EP2004/000210 - 53 Example 5 The amine derivatisation of the benzoxazinone is carried out analogously to the following scheme: 5 0 H H H 0 N N6 N N NH 2 10
R
10 or R or 15 CI
RI
0
-SO
2 CI or RIO- NCO 0 H 20 0 N H HI N NX 14 HN 'R IN O R'= COoR 1 0 , CORio, So 2
R
10 , CONHR 10 25 R4 has the meanings as indicated in Claim 1. 5.1 Sulfonylation: A solution of the amine 6 in absolute DMF is reacted at room temperature with 1.1 equivalents of an alkyl- or arylsulfonyl chloride and 3 equivalents 30 of triethylamine. After the reaction, the mixture is subjected to conventional work-up. Thus, reaction of ethyl 2-(S)-amino-3-{3-oxo-2-(R)-[2-(IH-imidazol-2-ylcarbamoyl) ethyl]-3,4-dihydro-2H-benzo[1, 4]oxazin-6-yl}propionate WO 2004/072054 PCT/IEP2004/000210 - 54 with butylsulfonyl chloride, 4-tolylsulfonyl chloride, benzylsulfonyl chloride, 5 (R or S)-camphor-1 0-sulfonyl chloride gives the following compounds ethyl 2-(S)-butylsulfonamido-3-{3-oxo-2-(R)-[2-(1H-imidazol-2-yl carbamoyl)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}propionate, 10 ethyl 2-(S)-(4-tolylsulfonamido)-3-{3-oxo-2-(R)-[2-(1H-imidazol-2-yl carbamoyl)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}propionate, ethyl 2-(S)-benzylsulfonamido-3-{3-oxo-2-(R)-[2-(1 H-imidazol-2-yl carbamoyl)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}propionate, ethyl 2-(S)-[(R)-camphor-1 0-ylsulfonamido]-3-{3-oxo-2-(R)-[2-(1 H 15 imidazol-2-ylcarbamoyl)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl} propionate, ethyl 2-(S)-[(S)-camphor-10-ylsulfonamido]-3-{3-oxo-2-(R)-[2-(1H imidazol-2-ylcarbamoyl)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl} propionate. 20 5.2 Carbamate formation A solution of the amine 5 in absolute DMF is reacted at room temperature with 1.1 equivalents of an alkyl or aryl chloroformate or with an alkyl or aryl 25 dicarbonate and 3 equivalents of triethylamine. After the reaction, the mixture is subjected to conventional work-up. Thus, reaction of ethyl 2-(S)-amino-3-{3-oxo-2-(R)-[2-(1H-imidazol-2-ylcarbamoyl) 30 ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}propionate with isopropyl chloroformate, benzyl chloroformate 35 gives the following compounds -55 ethyl 2-(S)-isobutoxycarboxamido-3-{3-oxo-2-(R)-[2-(1H-inidazol-2 ylcarbamoyl)ethyl]-34-dihydro-2H-benzo[1, 4 ]oxazin-6-yl}propionate, ethyl 2-(S)-benzyloxycarboxamido-3-{3-oxo-2-(R)-[2(1 H-imidazol-2 ylcarbamoyl)ethyl]-3,4-dihydro-2H-benzo[1, 4 ]oxazin-6-yl}propionate. 5 5.3 Acylation A solution of the amine 5 in absolute DMF is reacted at room temperature with 1. 1 equivalents of an alkyl- or arylcarbonyl chloride and 3 equivalents of triethylamine. After the reaction, the mixture is subjected to conventional 10 work-up. Alternatively, a very wide variety of variants can b.e employed, such as, for example, with EDCl, activated esters, HOBt/TBTU. 15 5.4 Urea formation A solution of the amine 5 in absolute DMF is reacted at room temperature with 1.1 equivalents of an alkyl or aryl isocyanate and 3 equivalents of triethylamine. After the reaction, the mixture is subjected to conventional work-up 20 The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as, an acknowledgement or admission or any form of suggestion that that prior publication 25 (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. 30 35

Claims (9)

1. Process for the preparation of compounds of the formula I 5 R3 O H 0 N R H 0 HN IX O4 R2 R 5 (CH2)2 10o in which R 1 denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or benzyl, denotes R 1 0 , CO-R O, COOR COOR, CONHR' , S0 2 R 6 or 15 S02R 10 R 3 denotes H or alkyl having 1-6 C atoms; R 4 denotes H, Hal, OA, NHR', N(R 1 ) 2 , -NH-acyl, -0-acyl, CN, NO 2 , OR'(, SR'(, R 2 or CONHR 10 R 5 denotes NH 2 , H 2 N-C(=NH) or H 2 N-(C=NH)-NH, where the pri 20 mary amino groups may also be provided with conventional amino-protecting groups, or may be mono-, di- or trisubsti tuted by R"', CO-R 10 COOR' or S02R' , or R, X is absent or denotes NH, 25R denotes a mono- or bicyclic saturated, unsaturated or aro matic heterocycle having 1 to 4 N, 0 and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, -. CO-A, OA, CN, COOH, COOA, CONHA, NO 2 , =NH or =0, R9 denotes H, Hal, OA, NHA, NAA', NHacyl, Oacyl, CN, NO 2 , 30 SA, SOA, SO 2 A, SO 2 Ph or SO 3 H, R 1 denotes H, A, Ar or aralkylene having 7-14 C atoms, A, A' each, independently of one another, denote H or alkyl or cycloalkyl having 1-15 C atoms, each of which is unsubstitu ted or mono-, di- or trisubstituted by R 9 and in which one, two 35 or three methylene groups may be replaced by N, 0 and/or g, - 57 Ar denotes mono- or bicyclic aromatic ring system having 0, 1 2, 3 or 4 N, 0 and/or S atoms which is unsubstituted or mono-, di- or trisubstituted by A and/or R 9 , Ph denotes phenyl which is unsubstituted or mono-, di- or trisub 5 stituted by A, Hal denotes F, Cl, Br or I and, and pharmaceutically usable salts, solvates and stereoisomers thereof, 10 where a) 5-oxotetrahydrofuran-2-carboxylic acid is reacted with a com pound of the formula il R 7 -L 7I 15 in which R 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and L denotes Cl, Br, I or.a free or reactively functionally modified OH group, 20 to give a compound of the formula Ill 0 0 R7 R 7 25 OH in which R denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, 30 b) then a compound of the formula Ill is reacted with a com pound of the formula IV R*-L IV in which 35 R denotes alkylsulfonyl having 1-6 C atoms or arylsulfonyl hav ing 6-10 C atoms and WO 2004/072054 PCT/EP2004/000210 - 58 L denotes CI, Br, I or a free or reactively functionally modified OH group, to give a compound of the formula V 5 0 0 R70O R7 V 10 R R 8 in which R 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and 15 R 8 denotes alkylsulfonyl having 1-6 C atoms or arylsulfonyl hav ing 6-10 C atoms, c) then a compound of the formula III or V is reacted with a compound of the formula VI 20 R3 0 0 2 N O 25 HO R2 VI R 4 in which R' denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or benzyl, 30 R denotes R 10 , CO-R'", COOR, COOR 1 0 , CONHR'", S0 2 R 6 or S0 2 R 0 , R 3 denotes H or alkyl having 1-6 C atoms, R 4 denotes H, Hal, OA, NHR 1 0 , N(R' 0 ) 2 , -NH-acyl, -0-acyl, CN, NO 2 , OR 10 , SR'", R 2 or CONHR'", 35 R 6 denotes a mono- or bicyclic saturated, unsaturated or aro matic heterocycle having 1 to 4 N, 0 and/or S atoms, which WO 2004/072054 PCTIEP2004/000210 - 59 may be unsubstituted or mono-, di- or trisubstituted by Hal, A, -CO-A, OA, CN, COOH, COOA, CONHA, NO 2 , =NH or =0, R9 denotes H, Hal, OA, NHA, NAA', NHacyl, Oacyl, CN, NO 2 , SA, SOA, SO 2 A, SO 2 Ph or SO 3 H, 5 R 1 0 denotes H, A, Ar or aralkylene having 7-14 C atoms, A, A' each, independently of one another, denote H or alkyl or cycloalkyl having 1-15 C atoms, each of which is unsubstitu ted or mono-, di- or trisubstituted by R 9 and in which one, two or three methylene groups may be replaced by N, 0 and/or 10 S, Ar denotes mono- or bicyclic aromatic ring system having 0, 1, 2, 3 or 4 N, 0 and/or S atoms which is unsubstituted or mono-, di- or trisubstituted by A and/or R 9 , Ph denotes phenyl which is unsubstituted or mono-, di- or 15 trisubstituted by A, Hal denotes F, Cl, Br or I, to give a compound of the formula VII 20 .R3 O R7 0 2 N O O HN O NR2 25 O R4 VII 0 O R7 30 in which R1 denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or benzyl, R 2 denotes R 1 0 , CO-R 1 0 , COOR , COOR' 0 , CONHR'", S0 2 R4 or S0 2 R 1 ", 35 R 3 denotes H or alkyl having 1-6 C atoms, WO 2004/072054 PCT/EP2004/000210 -60 R 4 denotes H, Hal, OA, NHR' 0 , N(R' 0 ) 2 , -NH-acyl, -0-acyl, CN, NO 2 , OR' 1 , SR' 1 , R 2 or CONHR'", R6 denotes a mono- or bicyclic saturated, unsaturated or aro matic heterocycle having 1 to 4 N, 0 and/or S atoms, which 5 may be unsubstituted or mono-, di- or trisubstituted by Hal, A, -CO-A, OA, CN, COOH, COOA, CONHA, NO 2 , =NH or =0, R' 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, R 9 denotes H, Hal, OA, NHA, NA', NHacyl, Oacyl, CN, NO 2 , SA, SOA, SO 2 A, SO 2 Ph or SO 3 H, 10 R 1 0 denotes H, A, Ar or aralkylene having 7-14 C atoms, A, A' each, independently of one another, denote H or alkyl or cycloalkyl having 1-15 C atoms, each of which is unsubstitu ted or mono-, di- or trisubstituted by R 9 and in which one, two or three methylene groups may be replaced by N, 0 and/or 15 S, Ar denotes mono- or bicyclic aromatic ring system having 0, 1, 2, 3 or 4 N, 0 and/or S atoms which is unsubstituted or mono-, di- or trisubstituted by A and/or R 9 , Ph denotes phenyl which is unsubstituted or mono-, di- or trisub 20 stituted by A, Hal denotes F, Cl, Br or I, d) then a compound of the formula Vil is converted into a com pound of the formula Vill 25 H R3 O H O N t o 1"R1 30 H O HN R2 HO Vill (CH 2 ) 2 R4 0 in which 35 R1 denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or benzyl, WO 2004/072054 PCT/EP2004/000210 -61 denotes R 1 0 , CO-R'", COOR , COOR 1 0 , CONHR, S0 2 R 6 or S0 2 R'", R 3 denotes H or alkyl having 1-6 C atoms, R 4 denotes H, Hal, OA, NHR 1 ", N(R' 0 ) 2 , -NH-acyl, -0-acyl, CN, 5 NO 2 , OR 1 0 , SR' 0 , R 2 or CONHR'", R" 6 denotes a mono- or bicyclic saturated, unsaturated or aro matic heterocycle having 1 to 4 N, 0 and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, -CO-A, OA, CN, COOH, COOA, CONHA, NO 2 , =NH or =0, 10 R 9 denotes H, Hal, OA, NHA, NAA', NHacyl, Oacyl, CN, NO 2 , SA, SOA, SO 2 A, SO 2 Ph or SO 3 H, R 1 0 denotes H, A, Ar or aralkylene having 7-14 C atoms, A, A' each, independently of one another, denote H or alkyl or cycloalkyl having 1-15 C atoms, each of which is unsubstitu 15 ted or mono-, di- or trisubstituted by R 9 and in which one, two or three methylene groups may be replaced by N, 0 and/or S, Ar denotes mono- or bicyclic aromatic ring system having 0, 1, 2, 3 or 4 N, 0 and/or S atoms which is unsubstituted or 20 mono-, di- or trisubstituted by A and/or R 9 , Ph denotes phenyl which is unsubstituted or mono-, di- or trisub stituted by A, Hal denotes F, Cl, Br or I, 25 e) subsequently, if desired, a compound of the formula Vill is converted into a compound of the formula Villa 0R3 0 30 0 - 0 ' Ri HL HNs L O R2 (CH 2 ) 2 R 4 VIlla 0 35 in which WO 2004/072054 PCT/EP2004/000210 -62 R', R 2 , R 3 and R 4 have the meanings indicated under d) and L denotes Cl, Br, I or a reactively functionally modified OH group, 5 e) then a compound of the formula Vill or a compound of the for mula Villa is reacted e) i) with a compound of the formula IX 10 R 5 -H IX in which R 5 denotes NH 2 , H 2 N-C(=NH) or H 2 N-(C=NH)-NH, where the pri mary amino groups may also be provided with conventional 15 amino-protecting groups, or may be mono-, di- or trisubsti tuted by R'", CO-R'", COOR 0 or S0 2 R' , in which R1a has the meanings indicated for the formula 1, or is reacted 20 e) ii) with a compound of the formula X R 6 -NH 2 X in which 25 R 6 denotes a mono- or bicyclic saturated, unsaturated or aro matic heterocycle having 1 to 4 N, 0 and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, -CO-A, OA, CN, COOH, COOA, CONHA, NO 2 , =NH or =0, 30 to give a compound of the formula 1, subsequently, if desired, a radical R 2 is converted into another radi cal R 2 by reacting a compound of the formula I in which R 2 denotes H 35 with a compound selected from the group -63 L-R', L-CO-R 0 , L-COOR, L-COOR 1 0 , R 10 -N=C=0, R 6 -SO 2 L, R 1 -SO2 L in which R 1 denotes A, Ar or aralkylene having 7-14 C atoms and 5 L denotes Cl, Br, I or a free or reactively functionally modified OH group, and/or a base or acid of the formula I is converted into one of its salts. 10
2. Process according to Claim 1, in which 3 denotes H R4 denotes H, 15 3. Process according to Claim 1 or 2, in which R 6 denotes 1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazol-2-yl, 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidin-4-on-5 yl, 1-A-1,5-dihydroimidazol-4-on-2-yl, pyrimidin-2-yi or 1,4,5,6-tetrahydropyrimidin-2-yl. 20
4. Process according to any one of Claims 1-3, in which R 9 denotes H.
5. Process according to any one of Claims 1-4, in which 25 R denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms, camphor
10-yl or benzyl. 6. Process according to any one of Claims 1-5, in which A denotes unsubstituted alkyl or cycloalkyl having 1-15 C 30 atoms. 7. Process according to any one of Claims 1-6, in which A denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms, R denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms, camphor 35 1 0-yl or benzyl. WO 2004/072054 PCT/EP2004/000210 -64 8. Process according to Claim 1, in which R' 1 denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or benzyl, R2 denotes R' , CO-R 1 , COOR 10 or S0 2 R'", R 3 denotes H, 5 R4 denotes H, R 5 denotes R , R 6 denotes a mono- or bicyclic saturated, unsaturated or aro matic heterocycle having 1 to 4 N, 0 and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, 10 -CO-A, OA, CN, COOH, COOA, CONHA, NO 2 , =NH or =0, X denotes NH, R 1 0 denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms, camphor 10-yl or benzyl, A denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms, 15 Hal denotes F, CI, Br or 1. 9. Process according to Claim 8, in which R 6 denotes 1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazol-2-yl, 2H-pyrazol-2-yi, 1H-tetrazol-5-yl, 2-iminoimidazolidin-4-on-5 20 yl, 1-A-1,5-dihydroimidazol-4-on-2-yI, pyrimidin-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl. 10. Process according to Claim 1 for the preparation of compounds of the formula la 25 H ~ R 3 O H O HN 30x 0< R4 R2 I 30 R5 (CH2)2 R 0 in which R1 denotes H or alkyl having 1, 2, 3 or 4 C atoms, 35 R 2 denotes R 1 0 , CO-R", COOR 10 orSO2R'O, R 3 denotes H, -65 denotes H, R 5 denotes R 6 X denotes NH, R6 denotes 1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazol-2-yl, 5 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidin-4-on-5 yl, 1-A-1,5-dihydroimidazol-4-on-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl, R 1 0 denotes H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and A denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms, 10 and pharmaceutically usable salts, solvates and stereoisomers thereof, where a) 5-oxotetrahydrofuran-2-carboxylic acid is reacted with a com 15 pound of the formula l1 R'-L 11 in which R denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and 20 L denotes Cl, Br, I or a free or reactively functionally modified OH group, to give a compound of the formula IlIl 25 O 0 R 7 O O OH 30 in which R 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, b) then a.compound of the formula Ill is reacted with a com pound of the formula IV 35 R 8 -L IV WO 2004/072054 PCT/EP2004/000210 -66 in which Ra 8 denotes alkylsulfonyl having 1-6 C atoms or arylsulfonyl hav ing 6-10 C atoms and L denotes Cl, Br, I or a free or reactively functionally modified 5 OH group, to give a compound of the formula V 10 0 0 R7 R7Y ~~0 R8 15 in which R 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and R8 denotes alkylsulfonyl having 1-6 C atoms or arylsulfonyl hav ing 6-10 C atoms, 20 c) then a compound of the formula III or V is reacted with a com pound of the formula VI 25 R3 0 251 0 2 N O 0 R I ~ HN HOR2 VI R4 30 in which R1 denotes H or alkyl having 1, 2, 3 or 4 C atoms, R2 denotes R'", CO-R'", COOR 10 or S0 2 R'*, R 3 denotes H, 35 R 4 denotes H, R 1 0 denotes H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and, WO 2004/072054 PCT/EP2004/000210 -67 to give a compound of the formula VII R3 O 5 R7-O 02N /N0R' O R2 0 R4 10 Vil R7 in which 15 R' denotes H or alkyl having 1, 2, 3 or 4 C atoms, R2 denotes R', CO-R'", COOR' or S0 2 R'", R 3 denotes H, R 4 denotes H, RT 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, 20 R 1 0 denotes H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, d) then a compound of the formula VII is converted into a com pound of the formula Vill 25 R3 O H HNR HO 0 R4 R Vill 30 (CH2)2 0 in which R1 denotes H or alkyl having 1, 2, 3 or 4 C atoms, R2 denotes R 10 , CO-R 10 , COOR 10 or SO 2 R'", R denotes H, R 4 denotes H, -68 R 1 0 denotes H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, e) then a compound of the formula VIII 5 is reacted with a compound of the formula X R 6 -NH 2 X in which R4 denotes 1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazol-2-yl, 10 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidin-4-on-5 yl, 1-A-1,5-dihydroimidazol-4-on-2-yl, pyrimidin-2-yl or 1, 4,5,6-tetrahydropyrimidin-2-yl, to give a compound of the formula la, 15 subsequently, if desired, a radical R 2 is converted into another radi cal R 2 by reacting a compound of the formula la in which R 2 denotes H with a compound selected from the group 20 L-R 10 , L-CO-R 0 , L-COOR 0 , Rl 0 -SO 2 L, in which R denotes alkyl having 1, 2,.3, 4, 5 or 6 C atoms and 25 L denotes Cl, Br, I or a free or reactively functionally modified OH group, and/or a base or acid of the formula la is converted into one of its salts. 30 11 Process according to any one of Claims 1-10, in which R 6 denotes 1H-imidazoi-2-yl. .12. Process according to anyone of Claims 1-11, in which 35 in step b), in the compounds of the formula IV and V, - 69 R9 denotes methylsulfonyl, trifluoromethylsulfonyl, phenyl sulfonyl or p-tolylsulfonyl. -13. Process according to any one of Claims 1-12, where the conver 5 sion of a compound of the formula VII into a compound of the formula VIII is carried out a) by reduction of the nitro group, subsequent ester cleavage and cyclisation or b) by ester cleavage, subsequent reduction of the nitro group 10 and cyclisation.
14. Process according to Claim 1 for the preparation of (S)-2-(2,2 dimethylpropoxycarbonylamino)-3-{(S)-2-[2-(I H-imidazol-2-yl carbamoyl)ethyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}propi 15 onic acid, where a) (S)-3-nitrotyrosine ethyl ester tosylate is reacted with 2,2 dimethylpropyl chloroformate to give ethyl (S)-2-(2,2-dimethyl 20 propoxycarbonylamino)-3-(4-hydroxy-3-nitrophenyl)propionate 12 b) 12 is reacted with dibenzyl 2-hydroxypentanedicarboxylate to give dibenzyl (R)-2-{4-[(S)-2-(2,2-dimethylpropoxycarbonylamino)-2 ethoxycarbonylethyl]-2-nitrophenoxy}pentanedicarboxylate 13 25 c) 13 is cyclised to give ethyl (2S)-3-[(2S)-2-(2-carboxyethyl)-3 oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-2-(2,2-dimethylpropoxy carbonylamino)propionate 14 30 d) 14 is reacted with 2-aminoimidazole to give ethyl 2-(S)-(2,2 dimethylpropoxycarbonylamino)-3-{3-oxo-2-(S)-[2-(1 H-imidazol-2-yl carbamoyl)ethyl]-3,4-dihydro-2H-benzo[1 ;4]oxazin-6-yl}propionate 15 and 35 WO 2004/072054 PCT/EP2004/000210 - 70 e) 15 is converted by ester cleavage into (S)-2-(2,2-dimethyl propoxycarbonylamino)-3-{(S)-2-[2-(1 H-imidazol-2-ylcarbamoyl) ethyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}propionic acid 16. 5 15. Intermediate compounds of the formula VII 10 0 HN 03 O R2 SR4 VII 15 R7 in which R1 denotes H or alkyl having 1, 2, 3 or 4 C atoms, 20 R2 denotes R'", CO-R 1 0 , COOR 10 or SO 2 R", R 3 denotes H, R 4 denotes H, RT 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, R9 denotes H, Hal, OA, NHA, NAA', NHacyl, Oacyl, CN, NO 2 , 25 SA, SOA, SO 2 A, SO 2 Ph or SO 3 H, R 10 denotes H, A, Ar or aralkylene having 7-14 C atoms, A, A' each, independently of one another, denote H or alkyl or cycloalkyl having 1-15 C atoms, each of which is unsubstitu ted or mono-, di- or trisubstituted by R 9 and in which one, two 30 or three methylene groups may be replaced by N, 0 and/or S, Ar denotes mono- or bicyclic aromatic ring system having 0, 1, 2, 3 or 4 N, 0 and/or S atoms, which is unsubstituted or mono-, di- or trisubstituted by A and/or R 9 , 35 and salts, solvates and stereoisomers thereof. -71
16. Process for the preparation of compounds of the formula VII, R 3 0 2Ra o 5 0 R O R4 vii o0 R 7 10 and salts, solvates and stereoisomers thereof, where a) 5-oxotetrahydrofuran-2-carboxylic acid is reacted with a com pound of the formula II 15 R-L -L in which R 7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and L denotes Cl, Br, I or a free or reactively functionally modified 20 OH group, to give a compound of the formula il 0 0 25 R7 OH in which R' denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, 30 b) then.a compound of the formula III is reacted with a compound of the formula IV R 8 -L IV 35 _72 in which R denotes alkylsulfonyl having 1-6 C atoms or arylsulfonyl hav ing 6-10 C atoms and. L denotes CI, Br, I or a free or reactively functionally modified 5 OH group, to give a compound of the formula V 0 0 10 R R 7 ~~0 R 8 15 in which R' denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and R 8 denotes alkylsulfonyl having 1-6 C atoms or arylsulfonyl hav ng 6-10 C atoms, 20 c) then a compound of the formula Ill or V is reacted with a com pound of the formula VI R3 O 25 02N O HN HO R 2 V1 R4 30 in which R 1 denotes H or alkyl having 1, 2, 3 or 4 C atoms, R 2 denotes R' 1 , CO-R 10 , COOR 1 0 or S0 2 R 1 0 , R 3 denotes H, R 4 denotes H, 35 -. R 9 denotes H, Hal, OA, NHA, NAA', NHacyl, Oacyl, CN, NO 2 , SA, SOA, SO 2 A, SO 2 Ph or SO 3 H, -73 R 1 0 denotes H, A, Ar or aralkylene having 7-14 C atoms, A, A' each, independently of one another, denote H or alkyl or cycloalkyl having 1-15 C atoms, each of which is unsubsti tuted or mono-, di- or trisubstituted by R 9 and in which one; 5 two or three methylene groups may be replaced by N, 0 and/or S, Ar . denotes mono- or bicyclic aromatic ring system having 0, 1, 2, 3 or 4 N, 0 and/or S atoms which is unsubstituted or mono-, 10 di- or trisubstituted by A ahd/or R 9 , to give a compound of the formula VII, and/or an acid of the formula VII is converted into one of its salts. 15
17. Processes for the preparation of compounds of formula I as defined in claim 1 or compounds of formula VII as defined in claim 16 substantially as herein described with reference to the Examples. 20
18. Compounds of formula I prepared by a process of claim 1 or compounds of formula VII prepared by a process of claim 16. 25 30 35 Editorial Note: Application No: 2004212029 The next page for Abstract starts from page 73.
AU2004212029A 2003-02-12 2004-01-14 Method for the production of bicyclic aromatic amino acids and intermediate products thereof Ceased AU2004212029B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10305784A DE10305784A1 (en) 2003-02-12 2003-02-12 3-Oxo-3,4-dihydro-2H-benz-(1,4)-oxazin-6-yl)-propionic acid derivative preparation, for use as integrin inhibitors with e.g. antitumor action, by multi-stage process giving diastereomerically pure product
DE10305784.6 2003-02-12
PCT/EP2004/000210 WO2004072054A1 (en) 2003-02-12 2004-01-14 Method for the production of bicyclic aromatic amino acids and intermediate products thereof

Publications (2)

Publication Number Publication Date
AU2004212029A1 AU2004212029A1 (en) 2004-08-26
AU2004212029B2 true AU2004212029B2 (en) 2010-01-21

Family

ID=32747754

Family Applications (1)

Application Number Title Priority Date Filing Date
AU2004212029A Ceased AU2004212029B2 (en) 2003-02-12 2004-01-14 Method for the production of bicyclic aromatic amino acids and intermediate products thereof

Country Status (15)

Country Link
US (1) US7371854B2 (en)
EP (1) EP1594853B1 (en)
JP (1) JP4709740B2 (en)
KR (1) KR20050105463A (en)
CN (1) CN1751034A (en)
AT (1) ATE400562T1 (en)
AU (1) AU2004212029B2 (en)
BR (1) BRPI0407377A (en)
CA (1) CA2515727C (en)
DE (2) DE10305784A1 (en)
ES (1) ES2308137T3 (en)
MX (1) MXPA05008440A (en)
PL (1) PL377556A1 (en)
WO (1) WO2004072054A1 (en)
ZA (1) ZA200507240B (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040063790A1 (en) * 1996-05-31 2004-04-01 The Scripps Research Institute Methods for inhibition of angiogenesis
WO2011024987A1 (en) * 2009-08-31 2011-03-03 塩野義製薬株式会社 Aromatic fused heterocyclic derivative and pharmaceutical composition containing same
US20180164221A1 (en) 2016-12-07 2018-06-14 Progenity Inc. Gastrointestinal tract detection methods, devices and systems
US20200253506A1 (en) 2016-12-14 2020-08-13 Progenity, Inc. Treatment of a disease of the gastrointestinal tract with an integrin inhibitor
EP3810085A1 (en) 2018-06-20 2021-04-28 Progenity, Inc. Treatment of a disease of the gastrointestinal tract with an integrin inhibitor
CN116726361A (en) 2018-11-19 2023-09-12 比奥拉治疗股份有限公司 Methods and devices for treating diseases with biologic therapeutic agents
WO2021119482A1 (en) 2019-12-13 2021-06-17 Progenity, Inc. Ingestible device for delivery of therapeutic agent to the gastrointestinal tract

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994029273A1 (en) * 1993-06-09 1994-12-22 Smithkline Beecham Corporation Bicyclic fibrinogen antagonists
JPH10510537A (en) * 1994-12-13 1998-10-13 スミスクライン・ビーチャム・コーポレイション Bicyclic fibrinogen antagonist
US6559144B2 (en) 1997-02-13 2003-05-06 Merck Patent Gesellschaft Mit Bicyclic amino acids
DE19705450A1 (en) * 1997-02-13 1998-08-20 Merck Patent Gmbh Bicyclic aromatic amino acids

Also Published As

Publication number Publication date
EP1594853B1 (en) 2008-07-09
ZA200507240B (en) 2006-06-28
US7371854B2 (en) 2008-05-13
AU2004212029A1 (en) 2004-08-26
ATE400562T1 (en) 2008-07-15
US20060142568A1 (en) 2006-06-29
KR20050105463A (en) 2005-11-04
JP2006517545A (en) 2006-07-27
PL377556A1 (en) 2006-02-06
WO2004072054A1 (en) 2004-08-26
BRPI0407377A (en) 2006-01-10
JP4709740B2 (en) 2011-06-22
ES2308137T3 (en) 2008-12-01
CN1751034A (en) 2006-03-22
DE502004007552D1 (en) 2008-08-21
EP1594853A1 (en) 2005-11-16
DE10305784A1 (en) 2004-08-26
MXPA05008440A (en) 2005-10-19
CA2515727C (en) 2012-02-21
CA2515727A1 (en) 2004-08-26

Similar Documents

Publication Publication Date Title
US6559144B2 (en) Bicyclic amino acids
CZ424998A3 (en) Phenylamine derivatives functioning as integrin inhibitors
CA2280727C (en) Bicyclic amino acids
SK412001A3 (en) Diacylhydrazine derivatives as integrin inhibitors
RU2234505C2 (en) Derivatives of chromenone and chromanone as integrin inhibitors
AU2004212029B2 (en) Method for the production of bicyclic aromatic amino acids and intermediate products thereof
SK11732001A3 (en) Beta-alanine derivatives
SK192002A3 (en) Diacylhydrazine derivatives, process for the preparation and use thereof and pharmaceutical composition comprising same
SK82099A3 (en) Cyclic peptide derivative, process for its preparation and pharmaceutical composition containing the same
US6521646B1 (en) Dibenzoazulene derivatives for treating thrombosis, osteoporosis, arteriosclerosis
SK1402002A3 (en) Fluorene derivative, process for the preparation thereof and pharmaceutical composition comprising same
MXPA98010586A (en) Phenylalanin derivatives as laintegr inhibitors
MXPA01004272A (en) Chromenone and chromanone derivatives as integrin inhibitors
MXPA99007464A (en) Bicyclic amino acids

Legal Events

Date Code Title Description
FGA Letters patent sealed or granted (standard patent)
MK14 Patent ceased section 143(a) (annual fees not paid) or expired